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Intellectual disability v3.194 KLF7 Arina Puzriakova Classified gene: KLF7 as Green List (high evidence)
Intellectual disability v3.194 KLF7 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases presenting the relevant phenotype.
Intellectual disability v3.194 KLF7 Arina Puzriakova Gene: klf7 has been classified as Green List (High Evidence).
Intellectual disability v3.193 KLF7 Arina Puzriakova Tag for-review tag was added to gene: KLF7.
Intellectual disability v3.193 KLF7 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P. Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.; to: Not associated with phenotype in OMIM or G2P.

Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.
Intellectual disability v3.193 KCNN3 Arina Puzriakova Added comment: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.
Intellectual disability v3.193 KCNN3 Arina Puzriakova Mode of pathogenicity for gene: KCNN3 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.192 KCNN3 Arina Puzriakova Classified gene: KCNN3 as Amber List (moderate evidence)
Intellectual disability v3.192 KCNN3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - three unrelated cases with relevant phenotype, although future re-evaluation of the two younger patients may be useful.
Intellectual disability v3.192 KCNN3 Arina Puzriakova Gene: kcnn3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.191 KCNN3 Arina Puzriakova Tag for-review tag was added to gene: KCNN3.
Intellectual disability v3.191 KCNN3 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and probable gene-disease association in G2P. Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia. ; to: Associated with phenotype in OMIM, and probable gene-disease association in G2P.

Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia.
Intellectual disability v3.191 GPC4 Arina Puzriakova Mode of inheritance for gene: GPC4 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.190 GPC4 Arina Puzriakova Classified gene: GPC4 as Amber List (moderate evidence)
Intellectual disability v3.190 GPC4 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases presenting the relevant phenotype.
Intellectual disability v3.190 GPC4 Arina Puzriakova Gene: gpc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.189 GPC4 Arina Puzriakova Tag for-review tag was added to gene: GPC4.
Tag Skewed X-inactivation tag was added to gene: GPC4.
Intellectual disability v3.189 GPC4 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and a confirmed gene in G2P. Amor et al. (2019) (PMID: 30982611) reported ten affected males from six familes, each harbouring distinct GPC4 variants. All identified variants were truncating or resulted in a frameshift, suggesting loss of function as the likely disease mechanism. Variable degrees of ID (mild-moderate) were reported in 8/10 participants. Some supporting functional data. ; to: Associated with phenotype in OMIM and a confirmed gene for Keipert syndrome in G2P.

Amor et al. (2019) (PMID: 30982611) reported ten affected males from six familes, each harbouring distinct GPC4 variants. All identified variants were truncating or resulted in a frameshift, suggesting loss of function as the likely disease mechanism. Variable degrees of ID (mild-moderate) were reported in 8/10 participants. Some supporting functional data.
Intellectual disability v3.189 IQSEC3 Arina Puzriakova Classified gene: IQSEC3 as Red List (low evidence)
Intellectual disability v3.189 IQSEC3 Arina Puzriakova Gene: iqsec3 has been classified as Red List (Low Evidence).
Intellectual disability v3.188 EIF2AK1 Arina Puzriakova Classified gene: EIF2AK1 as Red List (low evidence)
Intellectual disability v3.188 EIF2AK1 Arina Puzriakova Added comment: Comment on list classification: Phenotype not relevant to this panel.
Intellectual disability v3.188 EIF2AK1 Arina Puzriakova Gene: eif2ak1 has been classified as Red List (Low Evidence).
Intellectual disability v3.187 EIF2A Arina Puzriakova Classified gene: EIF2A as Red List (low evidence)
Intellectual disability v3.187 EIF2A Arina Puzriakova Gene: eif2a has been classified as Red List (Low Evidence).
Intellectual disability v3.186 DNM1L Arina Puzriakova Classified gene: DNM1L as Amber List (moderate evidence)
Intellectual disability v3.186 DNM1L Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases with distinct variants, presenting with a relevant phenotype.
Intellectual disability v3.186 DNM1L Arina Puzriakova Gene: dnm1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.185 DNM1L Arina Puzriakova Tag for-review tag was added to gene: DNM1L.
Intellectual disability v3.185 DNM1L Arina Puzriakova changed review comment from: Associated with related phenotype in OMIM and 'probable' gene in G2P. Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients: PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (68%) mosaicism was detected in the maternal sample.; to: Associated with related phenotype in OMIM and 'probable' gene in G2P.

Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients:

PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (6–8%) mosaicism was detected in the maternal sample. The second patient, with diffuse hypotonia, global developmental delay, poor growth, and persistent elevation of lactate, was found to harbour a de novo DNM1L variant (c.1135G>A, p.E379K). However, another de novo change in the PDHA1 gene (c.448G>A, p.G150R) was also found, and the definitive contribution of each variant to the patients phenotype could not be ascertained.

PMID: 27328748 - Compound heterozygous DNM1L variants (c.106A>G, p.Ser36Gly; c.346_347delGA, p.Glu116Lysfs*6) identified in two brothers (3 and 16-years-old) with psychomotor delay, ocular and cerebellar involvement, including mild cognitive impairment in the older brother. Some supporting functional evidence using patient fibroblasts and a yeast model.

PMID: 27301544 - De novo missense variant (c.1217T>C, p.Leu406Ser) identified in a child who presented severe hypotonia, infantile spasms with suppression‐burst and a high level of lactate in CSF. Development was profoundly delayed, and he attained no developmental milestones before his death at 18 months of age.

PMID: 26604000 - De novo missense substitution, (c.1085G>A; p.Gly362Asp) identified in a child with refractory epilepsy. Profound global developmental delay was reported, and at the last clinical assessment (age 7 years), he remained nonambulatory with the use of <10 monosyllabic words.

PMID: 26992161 - De novo heterozygous c.1084G>A (p.Gly362Ser) variant. Developmental delay was reported from 6-months of age, and at 2-years-old he was said to not be able to utter any intelligible words.

There are also reports of an identical de novo heterozygous missense variant (p.R403C) in four unrelated individuals who all experienced normal development until a sudden-onset episode of status epilepticus at the age of 4, 5, 10, and 11-years-old, respectively. Subsequently, all presented with rapid neurological regression, diffuse cerebral atrophy and substantial cognitive decline. Functional studies showed the variant confers a dominant negative effect (PMID: 27145208; 30767894; 30711678).
Intellectual disability v3.185 ATAD1 Arina Puzriakova Tag treatable tag was added to gene: ATAD1.
Tag for-review tag was added to gene: ATAD1.
Intellectual disability v3.185 ATAD1 Arina Puzriakova Classified gene: ATAD1 as Amber List (moderate evidence)
Intellectual disability v3.185 ATAD1 Arina Puzriakova Added comment: Comment on list classification: Multiple affected individuals from 3 unrelated families. There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.185 ATAD1 Arina Puzriakova Gene: atad1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.184 ATAD1 Arina Puzriakova changed review comment from: Not associated with any phenotype in G2P. Pathogenic variants have been described in seven affected individuals (three distinct consanguineous families) including a homozygous nonsense (c.826G>T; p.Glu276*), frameshift (c.1070_1071delAT; p.His357Argfs*15), and missense (c.162G>C; p.Gln54His) variant in the ATAD1 gene. Patients present with severe neurological features of essentially total absence of psychomotor development, encephalopathy, extreme hypertonia, non-responsiveness to stimuli, and death within the first few months of life. ; to: Not associated with any phenotype in G2P.

Pathogenic variants have been described in seven affected individuals (three distinct consanguineous families) including a homozygous nonsense (c.826G>T; p.Glu276*), frameshift (c.1070_1071delAT; p.His357Argfs*15), and missense (c.162G>C; p.Gln54His) variant in the ATAD1 gene. Patients present with severe neurological features of essentially total absence of psychomotor development, encephalopathy, extreme hypertonia, non-responsiveness to stimuli, and death within the first few months of life.

Knockout mouse model recapitulates phenotype. ATAD1 encodes Thorase, a mediator of AMPA receptor recycling; and therefore it was postulated that pathogenesis is a result of excessive AMPA receptor activity. Targeted therapy using perampanel, an AMPA receptor antagonist, ameliorated disease in both mice and humans, thus further supporting the role of ATAD1.
Intellectual disability v3.184 ADD3 Arina Puzriakova Classified gene: ADD3 as Amber List (moderate evidence)
Intellectual disability v3.184 ADD3 Arina Puzriakova Added comment: Comment on list classification: More than 3 unrelated individuals with ID. There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.184 ADD3 Arina Puzriakova Gene: add3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.183 ADD3 Arina Puzriakova Tag for-review tag was added to gene: ADD3.
Intellectual disability v3.183 ADD3 Arina Puzriakova changed review comment from: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID:23836506. PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy. ; to: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID: 23836506.

PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy.

PMID: 29768408 (2018) - Two families with ADD3 biallelic variants and one family with ADD3 and KAT2B missense variants. Individuals with ADD3 variants have similar phenotypes and individuals with KAT2B variants have an extension to phenotype with impaired kidney and heart function, also demonstrated with functional evidence in flies. ID was reported in 5/6 participants.
Intellectual disability v3.183 LZTFL1 Arina Puzriakova reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22510444, 23692385; Phenotypes: Bardet-Biedl syndrome 17, 615994; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 LYRM7 Arina Puzriakova reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: 24014394, 26912632, 28694194; Phenotypes: Mitochondrial complex III deficiency, nuclear type 8, 615838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 LIPT1 Arina Puzriakova reviewed gene: LIPT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24341803, 29681092, 31042466, 24256811, 27247813; Phenotypes: Lipoyltransferase 1 deficiency, 616299; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 KLF7 Arina Puzriakova reviewed gene: KLF7: Rating: GREEN; Mode of pathogenicity: ; Publications: 29251763; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 KCNN3 Arina Puzriakova reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 31155282; Phenotypes: Zimmermann-Laband syndrome 3, 618658; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 GPC4 Arina Puzriakova reviewed gene: GPC4: Rating: GREEN; Mode of pathogenicity: ; Publications: 30982611; Phenotypes: Keipert syndrome, 301026; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.183 IQSEC3 Arina Puzriakova reviewed gene: IQSEC3: Rating: RED; Mode of pathogenicity: ; Publications: 31130284; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 EIF2AK1 Arina Puzriakova reviewed gene: EIF2AK1: Rating: RED; Mode of pathogenicity: ; Publications: 32197074; Phenotypes: Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome, 618878, ADHD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.183 EIF2A Arina Puzriakova reviewed gene: EIF2A: Rating: RED; Mode of pathogenicity: ; Publications: 31130284; Phenotypes: Intellectual disability, Seizures, ASD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 DNM1L Arina Puzriakova reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: ; Publications: 27145208, 30767894, 30711678, 26931468, 27328748, 27301544, 26604000, 26992161; Phenotypes: Epileptic encephalopathy, 614388, Global developmental delay, Cerebral atrophy, Microcephaly; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.183 ATAD1 Arina Puzriakova reviewed gene: ATAD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28180185, 29390050, 29659736; Phenotypes: Encephalopathy, Progressive hypertonia, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.183 ADD3 Arina Puzriakova reviewed gene: ADD3: Rating: GREEN; Mode of pathogenicity: ; Publications: 23836506, 29768408; Phenotypes: Cerebral palsy, spastic quadriplegic, 617008, Intellectual disability, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.182 ASTN1 Arina Puzriakova Tag watchlist tag was added to gene: ASTN1.
Intellectual disability v3.182 ASTN1 Arina Puzriakova Classified gene: ASTN1 as Amber List (moderate evidence)
Intellectual disability v3.182 ASTN1 Arina Puzriakova Added comment: Comment on list classification: As limited segregation and case-specific details for the individual identified in the second study (PMID:27431290), rating Amber until further cases reported.
Intellectual disability v3.182 ASTN1 Arina Puzriakova Gene: astn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.181 ASTN1 Arina Puzriakova reviewed gene: ASTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26539891, 27431290, 29706646; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Classified gene: ASTN1 as Red List (low evidence)
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Added comment: Comment on list classification: Epilepsy only reported in a single patient. Further cases required to ascertain the contribution of ASTN1 variants to this phenotype.
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Gene: astn1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.126 ASTN1 Arina Puzriakova reviewed gene: ASTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26539891, 27431290, 29706646; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intracerebral calcification disorders v1.18 TINF2 Zornitza Stark gene: TINF2 was added
gene: TINF2 was added to Intracerebral calcification disorders. Sources: Expert list
Mode of inheritance for gene: TINF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TINF2 were set to 21477109; 18252230
Phenotypes for gene: TINF2 were set to Revesz syndrome, MIM# 268130
Review for gene: TINF2 was set to GREEN
gene: TINF2 was marked as current diagnostic
Added comment: Brain calcifications are part of the phenotype.
Sources: Expert list
Intracerebral calcification disorders v1.18 TYROBP Zornitza Stark gene: TYROBP was added
gene: TYROBP was added to Intracerebral calcification disorders. Sources: Expert list
Mode of inheritance for gene: TYROBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TYROBP were set to 30242731
Phenotypes for gene: TYROBP were set to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1, MIM# 221770
Review for gene: TYROBP was set to GREEN
Added comment: Brain calcifications are part of the phenotype.
Sources: Expert list
Intracerebral calcification disorders v1.18 RNASET2 Zornitza Stark gene: RNASET2 was added
gene: RNASET2 was added to Intracerebral calcification disorders. Sources: Expert list
Mode of inheritance for gene: RNASET2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASET2 were set to 19525954
Phenotypes for gene: RNASET2 were set to Leukoencephalopathy, cystic, without megalencephaly, MIM# 612951
Review for gene: RNASET2 was set to GREEN
gene: RNASET2 was marked as current diagnostic
Added comment: Intracranial calcification is a feature of this condition.
Sources: Expert list
Intellectual disability v3.181 GNAI2 Arina Puzriakova Classified gene: GNAI2 as Amber List (moderate evidence)
Intellectual disability v3.181 GNAI2 Arina Puzriakova Gene: gnai2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.180 FEM1B Arina Puzriakova Mode of inheritance for gene: FEM1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.179 FEM1B Arina Puzriakova edited their review of gene: FEM1B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Deleted their comment
Intellectual disability v3.179 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.179 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.179 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.179 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.179 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.179 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intellectual disability v3.178 FEM1B Arina Puzriakova Classified gene: FEM1B as Red List (low evidence)
Intellectual disability v3.178 FEM1B Arina Puzriakova Added comment: Comment on list classification: Although phenotypic overlap is noted, it is not possible to ascertain whether the additional cases refer to different individuals. Also possible founder effect as all cases harbour the same variant. Additional cases/functional data are required to ascertain the contribution of FEM1B variants to an ID phenotype.
Intellectual disability v3.178 FEM1B Arina Puzriakova Gene: fem1b has been classified as Red List (Low Evidence).
Intracerebral calcification disorders v1.18 FARSB Zornitza Stark gene: FARSB was added
gene: FARSB was added to Intracerebral calcification disorders. Sources: Expert list
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSB were set to 29573043; 19161147; 29979980; 30014610
Phenotypes for gene: FARSB were set to Rajab syndrome, MIM#613658; interstitial lung disease; brain calcifications; microcephaly; intellectual disability
Review for gene: FARSB was set to GREEN
gene: FARSB was marked as current diagnostic
Added comment: 7 unrelated families reported.
Sources: Expert list
Intellectual disability v3.177 FEM1B Arina Puzriakova changed review comment from: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional cases refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.; to: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher, who were said to share a similar phenotype. No function analysis was undertaken to validate the implication of FEM1B.
Lysosomal storage disorder v1.3 ATP13A2 Zornitza Stark gene: ATP13A2 was added
gene: ATP13A2 was added to Lysosomal storage disorder. Sources: Expert list
Mode of inheritance for gene: ATP13A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP13A2 were set to 28137957; 31996848
Phenotypes for gene: ATP13A2 were set to Spastic paraplegia 78, autosomal recessive, MIM# 617225
Review for gene: ATP13A2 was set to GREEN
gene: ATP13A2 was marked as current diagnostic
Added comment: Protein is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation.

PMID: 28137957 - 3 families with complicated hereditary spastic paraplegia. Supported by functional studies showing increased lysosomal size with aberrant material inside, and reduced lysosome activity.

PMID: 31996848 - protein acts as a lysosomal polyamine exporter. At high concentrations polyamines induce cell toxicity, which is exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture and cathepsin B activation.
Sources: Expert list
Lysosomal storage disorder v1.3 CTSF Zornitza Stark gene: CTSF was added
gene: CTSF was added to Lysosomal storage disorder. Sources: Expert list
Mode of inheritance for gene: CTSF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTSF were set to 28749476; 27668283; 27524508
Phenotypes for gene: CTSF were set to Ceroid lipofuscinosis, neuronal, 13, Kufs type, MIM# 615362
Review for gene: CTSF was set to GREEN
Added comment: Cathepsin is a member of the papain family of cysteine proteases, a major component of the lysosomal proteolytic system.

PMID: 28749476 - 1 chet patient (missense, CNV) with FTD, onset at 37 years old.

PMID: 27668283 - 2 families with adult-onset neuronal ceroid lipofuscinosis and FTD. Onset in 20s-30s. Light and electron microscopy shows swollen neuronal perikarya and intraneuronal storage of polymorphic lipofuscin-like inclusions

PMID: 27524508 - 1 hom family (PTC) with early-onset Alzheimer disease
Sources: Expert list
Laterality disorders and isomerism v1.8 CCDC32 Eleanor Williams Tag watchlist tag was added to gene: CCDC32.
Intellectual disability v3.177 CCDC32 Eleanor Williams Tag watchlist tag was added to gene: CCDC32.
Laterality disorders and isomerism v1.8 CCDC32 Eleanor Williams Classified gene: CCDC32 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.8 CCDC32 Eleanor Williams Added comment: Comment on list classification: Rating amber as 2 cases plus some functional evidence. Rating agreed with Genomics England clinical team.
Laterality disorders and isomerism v1.8 CCDC32 Eleanor Williams Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.7 CCDC32 Eleanor Williams Classified gene: CCDC32 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.7 CCDC32 Eleanor Williams Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.6 CCDC32 Eleanor Williams gene: CCDC32 was added
gene: CCDC32 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC32 were set to 32307552
Review for gene: CCDC32 was set to AMBER
Added comment: PMID: 32307552 - Harel et al 2020 - report 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32. Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.

The child in family 1 presented with cleft lip and palate, atrioventricular (AV) canal defect and abdominal situs inversus with asplenia, borderline microcephaly, hypotelorism, upslanting palpebral fissures, a stiff upper lip, missing teeth attributed to the clefting, vaulted palate with cleft, prominent ears, underdeveloped helices and micrognathia. The child in family 2 presented bilateral cleft lip, cleft palate, ventricular septal defect and pulmonary valve stenosis, Microcephaly (Z score−2.5), brachydactyly, hypertelorism, epicanthal folds, broad nasal root, a prominent large nose and malformed protruded ears.

Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and demonstrate a contribution of ccdc32 in craniofacial, brain and left/right axis development.
Sources: Literature
Intellectual disability v3.177 CCDC32 Eleanor Williams Classified gene: CCDC32 as Amber List (moderate evidence)
Intellectual disability v3.177 CCDC32 Eleanor Williams Added comment: Comment on list classification: Rating amber as 2 cases plus some limited functional evidence. Rating agreed with Genomics England clinical team.
Intellectual disability v3.177 CCDC32 Eleanor Williams Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.176 CCDC32 Eleanor Williams gene: CCDC32 was added
gene: CCDC32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC32 were set to 32307552
Phenotypes for gene: CCDC32 were set to global developmental delay
Review for gene: CCDC32 was set to AMBER
Added comment: PMID: 32307552 - Harel et al 2020 - report 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32.  Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.  In one family the child had global developmental delay, in the other the child had moderately delayed motor and language development and hyperactivity.

Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and demonstrate a contribution of ccdc32 in craniofacial, brain and left/right axis development.
Sources: Literature
Early onset or syndromic epilepsy v2.126 LIPT1 Sarah Leigh Publications for gene: LIPT1 were set to 29681092; 31042466
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Classified gene: LIPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Added comment: Comment on list classification: This metabolic gene is associated with Lipoyltransferase 1 deficiency 616299 in OMIM and as a probable gene for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. In addition to the six variants that have been reported in five cases Lipoyltransferase 1 deficiency 616299, two further variants have been reported in two unrelated cases of Lipoyltransferase 1 deficiency 616299 who also have epieptic seizures (PMID 29681092; 31042466).
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Gene: lipt1 has been classified as Amber List (Moderate Evidence).
Autosomal recessive congenital ichthyosis v1.9 ALDH3A2 Denise Williams gene: ALDH3A2 was added
gene: ALDH3A2 was added to Autosomal recessive congenital ichthyosis. Sources: Expert Review
Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH3A2 were set to 31273323; 27547594; 9829906
Phenotypes for gene: ALDH3A2 were set to congenital ichthyosis; intellectual disability; spastic diplegia, ocular anomalies.
Penetrance for gene: ALDH3A2 were set to Complete
Review for gene: ALDH3A2 was set to GREEN
Added comment: This is a well-recognised multi-systemic condition that can present with congenital ichthyosis. Early diagnosis is important to monitor other aspects of the condition.
Sources: Expert Review
Early onset or syndromic epilepsy v2.124 LIPT1 Sarah Leigh gene: LIPT1 was added
gene: LIPT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LIPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPT1 were set to 29681092; 31042466
Phenotypes for gene: LIPT1 were set to Lipoyltransferase 1 deficiency 616299
Review for gene: LIPT1 was set to AMBER
Added comment: Sources: Literature
Radial dysplasia v1.10 KCNH1 Zornitza Stark reviewed gene: KCNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Temple-Baraitser syndrome, MIM# 611816; Mode of inheritance: None
Cytopenias and congenital anaemias v1.73 NPM1 Zornitza Stark reviewed gene: NPM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31570891; Phenotypes: radial ray defects, short stature, nail dsytrophy, bone marrow failure; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Radial dysplasia v1.10 NPM1 Zornitza Stark gene: NPM1 was added
gene: NPM1 was added to Radial dysplasia. Sources: Expert list
Mode of inheritance for gene: NPM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPM1 were set to 31570891
Phenotypes for gene: NPM1 were set to radial ray defects; short stature; nail dsytrophy; bone marrow failure
Review for gene: NPM1 was set to GREEN
gene: NPM1 was marked as current diagnostic
Added comment: Recently reported association with a dyskeratosis congenita phenotype; supportive mouse model.
Sources: Expert list
Radial dysplasia v1.10 RAD21 Zornitza Stark reviewed gene: RAD21: Rating: GREEN; Mode of pathogenicity: None; Publications: 32193685; Phenotypes: Cornelia de Lange syndrome 4, MIM# 614701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Radial dysplasia v1.10 RAD51C Zornitza Stark reviewed gene: RAD51C: Rating: GREEN; Mode of pathogenicity: None; Publications: 29278735, 20400963; Phenotypes: Fanconi anemia, complementation group O 613390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Radial dysplasia v1.10 RPL15 Zornitza Stark reviewed gene: RPL15: Rating: GREEN; Mode of pathogenicity: None; Publications: 29599205; Phenotypes: Diamond-Blackfan anemia 12; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 RPS29 Zornitza Stark reviewed gene: RPS29: Rating: AMBER; Mode of pathogenicity: None; Publications: 24829207; Phenotypes: Diamond-Blackfan anemia 13, MIM# 615909; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lysosomal storage disorder v1.3 VPS33A Zornitza Stark gene: VPS33A was added
gene: VPS33A was added to Lysosomal storage disorder. Sources: Expert list
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 28013294; 27547915
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome (MIM#617303)
Review for gene: VPS33A was set to AMBER
Added comment: Single variant (R498W) reported in the Turkish and Yakut population. Functional studies support association of this gene to lysosomal dysfunction.
Sources: Expert list
Congenital disorders of glycosylation v2.14 TMEM199 Zornitza Stark reviewed gene: TMEM199: Rating: GREEN; Mode of pathogenicity: None; Publications: 26833330, 29321044; Phenotypes: Congenital disorder of glycosylation, type IIp MIM# 616829; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital disorders of glycosylation v2.14 STT3A Zornitza Stark reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23842455, 30701557, 28424003; Phenotypes: Congenital disorder of glycosylation, type Iw, OMIM #615596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital disorders of glycosylation v2.14 FUK Zornitza Stark gene: FUK was added
gene: FUK was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: FUK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUK were set to 30503518
Phenotypes for gene: FUK were set to Congenital disorder of glycosylation with defective fucosylation 2, MIM# 618324
Review for gene: FUK was set to AMBER
Added comment: Two unrelated individuals reported.
Sources: Expert list
Congenital disorders of glycosylation v2.14 CSGALNACT1 Zornitza Stark gene: CSGALNACT1 was added
gene: CSGALNACT1 was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: CSGALNACT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSGALNACT1 were set to 31705726; 31325655
Phenotypes for gene: CSGALNACT1 were set to Congenital disorder of glycosylation; skeletal dysplasia
Review for gene: CSGALNACT1 was set to GREEN
Added comment: Four unrelated families reported. CSGALNACT1 is predicted to transfer GalNAc to both the tetrasaccharide linker and to growing CS chains in proteoglycans.
Sources: Expert list
Congenital disorders of glycosylation v2.14 GMPPA Zornitza Stark gene: GMPPA was added
gene: GMPPA was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: GMPPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GMPPA were set to 24035193; 28574218
Phenotypes for gene: GMPPA were set to Alacrima, achalasia, and mental retardation syndrome (MIM# 615510)
Review for gene: GMPPA was set to GREEN
Added comment: Variants in this gene induce a significant GDP-mannose overload, which is postulated to affect protein glycosylation.

PMID: 24035193;
- 13 affecteds from 9 families
- GDP-mannose levels were shown to be increased in 2 of the affecteds

PMID: 28574218;
- 2 sisters with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism homozygous for c.853+1G>A.
- Loss of GMPPA protein leading to increased levels of GDP-mannose were demonstrated
Sources: Expert list
Congenital disorders of glycosylation v2.14 MAGT1 Zornitza Stark reviewed gene: MAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31036665, 31714901; Phenotypes: Congenital disorder of glycosylation, type Icc (MIM# 301031), Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Congenital disorders of glycosylation v2.14 EOGT Zornitza Stark gene: EOGT was added
gene: EOGT was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: EOGT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EOGT were set to 23522784; 31368252; 29924900
Phenotypes for gene: EOGT were set to Adams-Oliver syndrome 4, MIM# 615297
Review for gene: EOGT was set to GREEN
gene: EOGT was marked as current diagnostic
Added comment: Multiple families reported. EOGT is an O-linked-N-acetylglucosamine (O-GlcNAc) transferase, with modification restricted to the epidermal growth factor (EGF) domain-containing glycoproteins.
Sources: Expert list
Congenital disorders of glycosylation v2.14 POMK Zornitza Stark gene: POMK was added
gene: POMK was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: POMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POMK were set to 23519211; 24556084; 24925318
Phenotypes for gene: POMK were set to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 12 (MIM #615249)
Review for gene: POMK was set to GREEN
gene: POMK was marked as current diagnostic
Added comment: At least 3 families described with muscular dystrophy-dystroglycanopathy type A (PMID:23519211, 24556084, 24925318)

1 family described with muscular dystrophy-dystroglycanopathy type C (PMID:24925318)

The POMK gene encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex
Sources: Expert list
Congenital disorders of glycosylation v2.14 G6PC3 Zornitza Stark gene: G6PC3 was added
gene: G6PC3 was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: G6PC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: G6PC3 were set to 21385794
Phenotypes for gene: G6PC3 were set to Dursun syndrome 612541; Neutropenia, severe congenital 4, autosomal recessive 612541
Review for gene: G6PC3 was set to GREEN
gene: G6PC3 was marked as current diagnostic
Added comment: Multiple families reported. Deficiencies in G6PC3 impair the hydrolysis of glucose-6-phosphate to glucose. Patients’ neutrophils have both truncated and galactose-defective N- and O-glycans. 86 G6PC3 mutations cause severe congenital neutropenia (SCN) 4 (MIM: 612541) and Dursun syndrome (MIM: 612541). 83 The 119 G6PC3-CDG patients identified present with a wide range of immunological clinical manifestations and cellular/biochemical alterations.

4 unrelated families (PMID:21385794), profound hypo-galactosylation of N- and O-glycans. The observed defects in glycosylation merit the designation of congenital disorders of glycosylation (CDGs) to both syndromes.
Sources: Expert list
Congenital disorders of glycosylation v2.14 GORAB Zornitza Stark edited their review of gene: GORAB: Set current diagnostic: yes
Congenital disorders of glycosylation v2.14 GORAB Zornitza Stark reviewed gene: GORAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 18348262, 28807865, 30631079; Phenotypes: Geroderma osteodysplasticum MIM#231070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v2.14 B4GALNT1 Zornitza Stark gene: B4GALNT1 was added
gene: B4GALNT1 was added to Congenital disorders of glycosylation. Sources: Expert list
Mode of inheritance for gene: B4GALNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B4GALNT1 were set to 23746551; 24103911
Phenotypes for gene: B4GALNT1 were set to Spastic paraplegia 26, autosomal recessive (MIM #609195)
Review for gene: B4GALNT1 was set to GREEN
gene: B4GALNT1 was marked as current diagnostic
Added comment: 8 families described in total. The B4GALNT1 gene encodes beta-1,4-N-acetylgalactosaminyl transferase-1 (EC 2.4.1.92), an enzyme involved in the biosynthesis of complex gangliosides (G), which are mono- (M), di- (D), and tri- (T) sialic acid-containing glycosphingolipids generated by sequential glycosylations. (OMIM). 5 families with different homozygous variants described with complex hereditary spastic paraplegia (PMID: 23746551). Another 3 families with homozygous variants and progressive weakness and spasticity were described in PMID:24103911.
Sources: Expert list
Congenital disorders of glycosylation v2.14 SLC35A2 Zornitza Stark reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561849, 24115232, 27743886, 25778940, 30817854; Phenotypes: Congenital disorder of glycosylation, type IIm (MIM #300896); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Cutaneous photosensitivity with a likely genetic cause v1.3 GATA1 Zornitza Stark changed review comment from: Can only find two reports in the literature, same missense variant: PMID: 17148589 - 1 hemizygous English/French patient with p.R216W and photosensitive bullous dermatosis. PMID: 25251786 - 1 hemizygous Turkish patient with p.R216W and photosensitive bullous dermatosis.; to: Can only find two reports in the literature for this phenotype, same missense variant: PMID: 17148589 - 1 hemizygous English/French patient with p.R216W and photosensitive bullous dermatosis. PMID: 25251786 - 1 hemizygous Turkish patient with p.R216W and photosensitive bullous dermatosis.
Cutaneous photosensitivity with a likely genetic cause v1.3 GATA1 Zornitza Stark reviewed gene: GATA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 17148589, 25251786; Phenotypes: Erythropoietic porphyria; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cutaneous photosensitivity with a likely genetic cause v1.3 HMBS Zornitza Stark reviewed gene: HMBS: Rating: AMBER; Mode of pathogenicity: None; Publications: 32377710, 29731767, 25419136, 32197664, 30071891; Phenotypes: Porphyria, acute intermittent (MIM#176000); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v2.11 KIAA0825 Zornitza Stark gene: KIAA0825 was added
gene: KIAA0825 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: KIAA0825 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0825 were set to 32147526; 30982135
Phenotypes for gene: KIAA0825 were set to Polydactyly, postaxial, type A10, MIM# 618498
Review for gene: KIAA0825 was set to GREEN
gene: KIAA0825 was marked as current diagnostic
Added comment: Three families reported.
Sources: Literature
Peroxisomal disorders v1.6 NSDHL Zornitza Stark changed review comment from: Enzyme localised to ER rather than peroxisomes.; to: Enzyme localises to ER rather than peroxisomes.
Peroxisomal disorders v1.6 NSDHL Zornitza Stark edited their review of gene: NSDHL: Changed rating: RED
Peroxisomal disorders v1.6 NSDHL Zornitza Stark reviewed gene: NSDHL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Peroxisomal disorders v1.6 HOGA1 Zornitza Stark reviewed gene: HOGA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperoxaluria, primary, type III (MIM#613616); Mode of inheritance: None
Peroxisomal disorders v1.6 GRHPR Zornitza Stark reviewed gene: GRHPR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Peroxisomal disorders v1.6 FAR1 Zornitza Stark reviewed gene: FAR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25439727; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder (MIM#616154); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Peroxisomal disorders v1.6 AGK Zornitza Stark reviewed gene: AGK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cataract 38, autosomal recessive, MIM# 614691, Sengers syndrome, MIM# 212350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Peroxisomal disorders v1.6 ACBD5 Zornitza Stark gene: ACBD5 was added
gene: ACBD5 was added to Peroxisomal disorders. Sources: Expert list
Mode of inheritance for gene: ACBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD5 were set to 27799409; 23105016
Phenotypes for gene: ACBD5 were set to Retinal dystrophy with leukodystrophy (MIM#618863)
Review for gene: ACBD5 was set to GREEN
gene: ACBD5 was marked as current diagnostic
Added comment: 2 families reported and supporting in vitro functional assays demonstrating ACBD5 deficiency leading to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation PMID: 27799409: 1 patient girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. Functional assay supports ACBD5 deficiency leads to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation PMID: 23105016: 1 family retinal dystrophy.
Sources: Expert list
Glycogen storage disease v1.4 RBCK1 Zornitza Stark gene: RBCK1 was added
gene: RBCK1 was added to Glycogen storage disease. Sources: Expert list
Mode of inheritance for gene: RBCK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBCK1 were set to 23798481; 23104095
Phenotypes for gene: RBCK1 were set to Polyglucosan body myopathy 1 with or without immunodeficiency MIM#615895
Review for gene: RBCK1 was set to GREEN
gene: RBCK1 was marked as current diagnostic
Added comment: Biallelic variants cause polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy, which is characterised as a glycogen storage disorder. At least 9 families reported.
Sources: Expert list
Hypogonadotropic hypogonadism (GMS) v1.8 NSMF Zornitza Stark reviewed gene: NSMF: Rating: RED; Mode of pathogenicity: None; Publications: 15362570, 17235395, 21700882; Phenotypes: Hypogonadotropic hypogonadism 9 with or without anosmia, MIM# 614838; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v1.8 SOX10 Zornitza Stark reviewed gene: SOX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23643381, 15004559; Phenotypes: PCWH syndrome (MIM#609136), Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584), Waardenburg syndrome, type 4C (MIM#613266); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v1.8 KLB Zornitza Stark reviewed gene: KLB: Rating: GREEN; Mode of pathogenicity: None; Publications: 28754744; Phenotypes: Hypogonadotropic hypogonadism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Hypogonadotropic hypogonadism (GMS) v1.8 IL17RD Zornitza Stark reviewed gene: IL17RD: Rating: AMBER; Mode of pathogenicity: None; Publications: 23643382, 32389901; Phenotypes: Hypogonadotropic hypogonadism 18 with or without anosmia, MIM# 615267; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Differences in sex development v2.4 HOXA13 Zornitza Stark gene: HOXA13 was added
gene: HOXA13 was added to Disorders of sex development. Sources: Expert list
Mode of inheritance for gene: HOXA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXA13 were set to 10839976; 9020844
Phenotypes for gene: HOXA13 were set to Hand-foot-uterus syndrome, MIM# 140000
Review for gene: HOXA13 was set to GREEN
gene: HOXA13 was marked as current diagnostic
Added comment: Hypospadias/bifid scrotum in males, Mullerian duct fusion defects in females (double uterus, double cervix, longitudinal vaginal septum).
Sources: Expert list
Hypogonadotropic hypogonadism (GMS) v1.8 GNRH1 Zornitza Stark reviewed gene: GNRH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19535795, 19567835, 32134721, 31200363, 26595427; Phenotypes: Hypogonadotropic hypogonadism 12 with or without anosmia, MIM# 614841; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed rating: RED
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed publications: 21336785, 28736820, 29180453, 29691679, 31236401; Changed phenotypes: Neuropathy, hereditary sensory, type ID, MIM# 613708, Spastic paraplegia 3A, autosomal dominant, MIM# 182600
Intellectual disability v3.175 ATL1 Zornitza Stark changed review comment from: Please note additional recent publications. Principal association is with HSP phenotype, often of later onset. Few reports of intellectual disability as part of this condition.; to: Please note additional recent publications. Principal association is with HSP/neuropathy phenotype, often of later onset. Few reports of intellectual disability as part of this condition (two families).
Intellectual disability v3.175 ATL1 Zornitza Stark changed review comment from: Please note additional recent publications; to: Please note additional recent publications. Principal association is with HSP phenotype, often of later onset. Few reports of intellectual disability as part of this condition.
Intellectual disability v3.175 ATL1 Zornitza Stark edited their review of gene: ATL1: Changed rating: AMBER
Distal myopathies v1.20 GIPC1 Zornitza Stark gene: GIPC1 was added
gene: GIPC1 was added to Distal myopathies. Sources: Literature
Mode of inheritance for gene: GIPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIPC1 were set to 32413282
Phenotypes for gene: GIPC1 were set to Oculopharyngodistal myopathy-2 (OPDM2), MIM#618940
Mode of pathogenicity for gene: GIPC1 was set to Other
Review for gene: GIPC1 was set to GREEN
Added comment: 19 families reported with heterozygous trinucleotide repeat expansion in the 5-prime untranslated region and onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. Note this is unlikely to be tractable currently by most NGS assays, and may be best dealt with as an STR disorder here.
Sources: Literature
Intellectual disability v3.175 ATL1 Sarah Leigh commented on gene: ATL1: The "for-review" tag has been added to this gene as there is enough evidence for this gene to be rated RED at the next major review.
Intellectual disability v3.175 ATL1 Sarah Leigh changed review comment from: Associated with phenotype in OMIM, not in G2P. Mild late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600; to: Associated with phenotype in OMIM, not in G2P. Mild to severe late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600
Intellectual disability v3.175 ATL1 Sarah Leigh Tag for-review tag was added to gene: ATL1.
Intellectual disability v3.175 ATL1 Sarah Leigh commented on gene: ATL1: Associated with phenotype in OMIM, not in G2P. Mental retardation has been reported in a second family (PMID 31236401). In this publication, the 9 year old proband and his maternal grandfather had hereditary spastic paraplegia and intellectual disability, however, proband's mother had hereditary spastic paraplegia, but no intelectual disability.
Fetal anomalies v1.74 NONO Suzanne Drury reviewed gene: NONO: Rating: ; Mode of pathogenicity: None; Publications: 32397791; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.175 ATL1 Sarah Leigh Publications for gene: ATL1 were set to 21336785; 28736820; 29180453; 29691679
Intellectual disability v3.174 FEM1B Arina Puzriakova changed review comment from: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.; to: Gene not associated with any phenotype on OMIM or G2P.

Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery study and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional cases refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.
Early onset or syndromic epilepsy v2.123 PTPN23 Eleanor Williams Added comment: Comment on phenotypes: Added disease association from OMIM.
Early onset or syndromic epilepsy v2.123 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Rare severe autosomal-recessive developmental and epileptic encephalopathy to Rare severe autosomal-recessive developmental and epileptic encephalopathy; Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity MIM#618890
Intellectual disability v3.174 PTPN23 Eleanor Williams Added comment: Comment on phenotypes: Added disease association from OMIM.
Intellectual disability v3.174 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Developmental epileptic encephalopathy with hypomyelination and brain atrophy; Intellectual disability; Severe developmental delay, to Developmental epileptic encephalopathy with hypomyelination and brain; Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity MIM#618890 atrophy; Intellectual disability; Severe developmental delay,
Intellectual disability v3.173 GRIA2 Eleanor Williams Added comment: Comment on phenotypes: Added disease association which has been added to OMIM.
Intellectual disability v3.173 GRIA2 Eleanor Williams Phenotypes for gene: GRIA2 were changed from Epileptic encephalopathy intellectual disability stereotypic hand movements to Epileptic encephalopathy intellectual disability stereotypic hand movements; Neurodevelopmental disorder with language impairment and behavioral abnormalities MIM#618917
Intellectual disability v3.172 FBXW11 Eleanor Williams Added comment: Comment on phenotypes: Added disease association which has been added in OMIM.
Intellectual disability v3.172 FBXW11 Eleanor Williams Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914
Intellectual disability v3.171 CARS Eleanor Williams Added comment: Comment on phenotypes: Added disease term which has now been added to OMIM.
Intellectual disability v3.171 CARS Eleanor Williams Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay to Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891
COVID-19 research v1.60 FPR2 Eleanor Williams Publications for gene: FPR2 were set to
Differences in sex development v2.4 GATA4 Zornitza Stark reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21220346, 31962012; Phenotypes: Testicular anomalies with or without congenital heart disease, MIM#615542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Congenital disorders of glycosylation v2.14 TRAPPC11 Zornitza Stark reviewed gene: TRAPPC11: Rating: AMBER; Mode of pathogenicity: None; Publications: 23830518, 26322222, 29855340, 30105108, 26912795, 27707803, 27862579, 28484880; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 18 MIM# 615356; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism (GMS) v1.8 LEP Zornitza Stark gene: LEP was added
gene: LEP was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list
Mode of inheritance for gene: LEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LEP were set to 26567097; 31483094
Phenotypes for gene: LEP were set to Obesity, morbid, due to leptin deficiency (MIM#614962)
Review for gene: LEP was set to GREEN
gene: LEP was marked as current diagnostic
Added comment: Hypogonadotropic hypogonadism is a feature of congenital leptin deficiency.
Sources: Expert list
Differences in sex development v2.4 FGFR2 Zornitza Stark gene: FGFR2 was added
gene: FGFR2 was added to Disorders of sex development. Sources: Expert list
Mode of inheritance for gene: FGFR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGFR2 were set to 26362256; 18155190
Phenotypes for gene: FGFR2 were set to LADD syndrome 149730; Bent bone dysplasia syndrome 614592
Review for gene: FGFR2 was set to GREEN
Added comment: PMID: 26362256 - 1 individual with craniosynostosis and XY sex reversal and a missense variant. Phenotype recapitulated using mouse model, concludes a LOF mechanism.

PMID: 18155190 - partial null mutant mouse model shows XY sex reversal

PMID: 2238701 - 4 fetuses with de novo mutations and a skeletal disorder 3/4 had clitoromegaly, last fetus only had radiograph available. p.(Met391Arg) is recurring, variants are supported by functional studies showing protein mislocalization

Mutations reported for all other FGFR2-related conditions have a GOF mechanism
Sources: Expert list
Hypogonadotropic hypogonadism (GMS) v1.8 LEPR Zornitza Stark gene: LEPR was added
gene: LEPR was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list
Mode of inheritance for gene: LEPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LEPR were set to 17229951; 29545012
Phenotypes for gene: LEPR were set to Obesity, morbid, due to leptin receptor deficiency (MIM#614963)
Review for gene: LEPR was set to GREEN
gene: LEPR was marked as current diagnostic
Added comment: >5 families reported. Hypogonadotropic hypogonadism is a feature of the phenotype.
Sources: Expert list
Hypogonadotropic hypogonadism (GMS) v1.8 FGF17 Zornitza Stark gene: FGF17 was added
gene: FGF17 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list
Mode of inheritance for gene: FGF17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF17 were set to 23643382; 31748124
Phenotypes for gene: FGF17 were set to Hypogonadotropic hypogonadism 20 with or without anosmia, MIM# 615270
Penetrance for gene: FGF17 were set to Incomplete
Review for gene: FGF17 was set to AMBER
Added comment: PMID: 23643382 - 3 individuals with Kallman syndrome or idiopathic hypogonadotropic hypogonadism (IHH). Functional studies on missense showed reduced protein expression and destabilization, one individual had additional variants in other genes.

PMID: 31748124 - 3 individuals with IHH, where two individuals inherited variants from unaffected parents.
Sources: Expert list
Differences in sex development v2.4 ESR2 Zornitza Stark gene: ESR2 was added
gene: ESR2 was added to Disorders of sex development. Sources: Expert list
Mode of inheritance for gene: ESR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ESR2 were set to 29261182; 9861029; 30113650
Phenotypes for gene: ESR2 were set to 46,XY disorder of sex development; Ovarian dysgenesis 8, MIM# 618187
Review for gene: ESR2 was set to AMBER
Added comment: A homozygous indel (Asn181del) was identified in a syndromic case with 46,XY DSD, and 2 heterozygous missense variants were identified in 2 non-syndromic cases with 46,XY DSD. Asn181del and Leu426Arg were found to have significantly increased transcriptional activation in in vitro luciferase assays. Esrb null male mice showed no overt abnormalities and reproduced normally. Older mutant males displayed signs of prostate and bladder hyperplasia.
A further individual reported with 46,XX karyotype and ovarian dysgenesis (PMID: 30113650)
Sources: Expert list
Hypogonadotropic hypogonadism (GMS) v1.8 DUSP6 Zornitza Stark gene: DUSP6 was added
gene: DUSP6 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list
Mode of inheritance for gene: DUSP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DUSP6 were set to 23643382; 32389901
Phenotypes for gene: DUSP6 were set to Hypogonadotropic hypogonadism 19 with or without anosmia, MIM# 615269
Review for gene: DUSP6 was set to GREEN
gene: DUSP6 was marked as current diagnostic
Added comment: PMID: 23643382 - 5 individuals with congenital hypogonadotrophic hypogonadism (CHH) (3 carry additional variants in FGFR1, SPRY4) PMID: 32389901 - 6 individuals with isolated HH, 3 also had cryptorchidism.
Sources: Expert list
Congenital disorders of glycosylation v2.14 PIGW Zornitza Stark reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 24367057, 27626616, 30813920, 32198969; Phenotypes: intractable seizures, West syndrome, severe developmental delay, dysmorphic facial features, hyperphosphatasia, epilepsy, recurrent respiratory infections, hypotonia, stereotypies, Glycosylphosphatidylinositol biosynthesis defect 11, MIM# 616025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Differences in sex development v2.4 MYRF Zornitza Stark reviewed gene: MYRF: Rating: GREEN; Mode of pathogenicity: None; Publications: 30985895, 29446546, 31069960, 30070761, 30532227; Phenotypes: Cardiac-urogenital syndrome, gonadal hypoplasia, Müllerian duct hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Differences in sex development v2.4 NR3C1 Zornitza Stark gene: NR3C1 was added
gene: NR3C1 was added to Disorders of sex development. Sources: Expert list
Mode of inheritance for gene: NR3C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR3C1 were set to 30158362
Phenotypes for gene: NR3C1 were set to Glucocorticoid resistance (MIM#615962)
Review for gene: NR3C1 was set to GREEN
gene: NR3C1 was marked as current diagnostic
Added comment: Features include hyperandrogenism with features of ambiguous genitalia, precocious puberty, advanced bone age, infertility, amenorrhea, clitoromegaly, oligospermia. PMID: 30158362: Review of >5 patients reported with the associated phenotype.
Sources: Expert list
DDG2P v2.9 ABCC9 Tracy Lester reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: None; Publications: 31575858; Phenotypes: mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v2.22 AFG3L2 Ivone Leong Phenotypes for gene: AFG3L2 were changed from SPASTIC ATAXIA 5, AUTOSOMAL RECESSIVE, 614487; SPINOCEREBELLAR ATAXIA 28, 610246 to Spastic ataxia 5, autosomal recessive, 614487; Spinocerebellar ataxia 28, 610246
Optic neuropathy v2.21 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to 29181157; 26539208; 30544562
Optic neuropathy v2.20 AP3B2 Ivone Leong Classified gene: AP3B2 as Amber List (moderate evidence)
Optic neuropathy v2.20 AP3B2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. AP3B2 is associated with a relevant disease in OMIM and probably associated with a relevant disease in Gene2Phenotype. There is enough evidence for this gene to be Green; however, until the next major review this gene will be rated as Amber for now.
Optic neuropathy v2.20 AP3B2 Ivone Leong Gene: ap3b2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.19 AP3B2 Ivone Leong Tag for-review tag was added to gene: AP3B2.
Optic neuropathy v2.19 AP3B2 Ivone Leong Phenotypes for gene: AP3B2 were changed from Early-onset epileptic encephalopathy with optic atrophy, MIM#617276 to Epileptic encephalopathy, early infantile, 48, 617276
Early onset or syndromic epilepsy v2.122 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures, which were intractable in three of the individuals. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function

This gene has also been added to the Intellectual Disability and Severe Microcephaly panels with a suggested Green classification at the next major review.
Severe microcephaly v2.11 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Affected individuals were microcephalic at birth or developed postnatal microcephaly ranging from -3.6 to -4.0 SD. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545).

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function

This gene has also been added to the Genetic Epilepsy and Intellectual Disability panels with a suggested Green classification at the next major review.
Intellectual disability v3.170 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function.

This gene has also been added to the Genetic Epilepsy and Severe Microcephaly panels with a suggested Green classification at the next major review.
Fetal anomalies v1.74 SNAP29 Rhiannon Mellis reviewed gene: SNAP29: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 15968592, 21073448, 28388629; Phenotypes: CEDNIK syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v2.18 ATAD3A Ivone Leong Added comment: Comment on mode of inheritance: Changed MOI from Both monoallelic and biallelic to Monoallelic only as it is patients with the Monoallelic form had optic atrophy (PMID: 27640307). Patients with biallelic variants had congenital cataract.
Optic neuropathy v2.18 ATAD3A Ivone Leong Mode of inheritance for gene: ATAD3A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Optic neuropathy v2.17 ATAD3A Ivone Leong Publications for gene: ATAD3A were set to 27640307
Optic neuropathy v2.16 FDXR Ivone Leong Classified gene: FDXR as Amber List (moderate evidence)
Optic neuropathy v2.16 FDXR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark.

This gene is associated with a relevant disease in OMIM. PMID: 2499495 describes a FDXR KO mouse model that had progressive optic neuropathy. Based on all the available evidence there is enough evidence to promote this gene to Green status, which will be done at the next major review. Therefore, this gene has been rated as Amber for now.
Optic neuropathy v2.16 FDXR Ivone Leong Gene: fdxr has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.15 FDXR Ivone Leong Tag for-review tag was added to gene: FDXR.
Optic neuropathy v2.15 FDXR Ivone Leong Publications for gene: FDXR were set to 30250212; 28965846; 29040572
Optic neuropathy v2.14 MCAT Ivone Leong Classified gene: MCAT as Red List (low evidence)
Optic neuropathy v2.14 MCAT Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Based on the evidence this gene has been rated as Red as there is only 1 reported case.
Optic neuropathy v2.14 MCAT Ivone Leong Gene: mcat has been classified as Red List (Low Evidence).
Intellectual disability v3.170 CNPY3 Konstantinos Varvagiannis gene: CNPY3 was added
gene: CNPY3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CNPY3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNPY3 were set to 29394991; 30237576
Phenotypes for gene: CNPY3 were set to Epileptic encephalopathy, early infantile, 60 (MIM 617929)
Penetrance for gene: CNPY3 were set to Complete
Review for gene: CNPY3 was set to GREEN
Added comment: Biallelic CNPY3 mutations cause Epileptic encephalopathy, early infantile, 60 (MIM 617929).

The phenotype including among others hypotonia, intractable seizures, DD and ID has been first reported by Mutoh et al (2018 - PMID: 29394991) in 3 subjects from 2 families. Evidence was provided for the role of the gene (incl. mouse model) and pathogenicity of the identified variants (resulting in LoF).

Another subject with similar features of hypotonia, DD, intractable epilepsy, feeding problems has been described briefly by Maddirevula et al (2019 - PMID: 30237576).
Sources: Literature
Intellectual disability v3.170 KIF21B Konstantinos Varvagiannis gene: KIF21B was added
gene: KIF21B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Penetrance for gene: KIF21B were set to unknown
Mode of pathogenicity for gene: KIF21B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Literature
Fetal anomalies v1.74 CEP120 Rhiannon Mellis gene: CEP120 was added
gene: CEP120 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CEP120 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP120 were set to PMID: 2720821; 25361962
Phenotypes for gene: CEP120 were set to Joubert syndrome 31; Short-rib thoracic dysplasia 13 with or without polydactyly
Review for gene: CEP120 was set to GREEN
Added comment: PMID: 27208211 identifies CEP120 variants in 6 unrelated families, segregating with disease within the families, including four children with milder Joubert phenotype and two fetuses with prenatal phenotypes of more severe ciliopathy.

PMID: 25361962 describes 4 unrelated infants, 3 male and 1 female, with short-rib thoracic dysplasia and polydactyly (SRTD).

CEP120 is rated Green on the following PanelApp panels: Thoracic dystrophies, Skeletal dysplasia, Skeletal ciliopathies, Rare multisystem ciliopathy disorders.
Sources: Literature
Intellectual disability v3.170 PAX1 Konstantinos Varvagiannis gene: PAX1 was added
gene: PAX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PAX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX1 were set to 29681087; 23851939; 28657137
Phenotypes for gene: PAX1 were set to Otofaciocervical syndrome 2, 615560
Penetrance for gene: PAX1 were set to Complete
Review for gene: PAX1 was set to AMBER
Added comment: Biallelic PAX1 pathogenic variants cause Otofaciocervical syndrome 2 (OMIM 615560).

Brief review of the literature suggests 3 relevant publications to date (04-07-2020).

2 individuals with DD and ID have been reported (Patil et al, 2018 - PMID: 29681087 and Pohl et al, 2013 - PMID: 23851939). Other subjects reported were only evaluated as newborns(mostly)/infants [Paganini et al, 2017 - PMID: 28657137, Patil et al, 2018 - PMID: 29681087].

While the first report by Pohl et al identified a homozygous missense variant supported by functional studies [NM_006192.5:c.497G>T - p.(Gly166Val)] subsequent ones identified homozygosity for pLoF mutations [Patil et al: NM_006192.4:c.1173_1174insGCCCG / Paganini et al: NM_006192:c.1104C>A - p.(Cys368*)].

As discussed by Pohl et al:

PAX1 encodes a transcription factor with critical role in pattern formation during embryogenesis. Study of the mouse Gly157Val (equivalent to human Gly166Val) Pax1 variant suggested reduced binding affinity (reduced transactivation of a regulatory sequence of the Nkx3-2 promoter) and hypofunctional nature of this variant.

Mouse models seem to recapitulate features of the disorder (skeletal, immunodeficiency) while the role of Pax1 in hearing process was thought to be supported by early expression (P6) in mouse cochlea.

Overall this gene can be considered for inclusion in the ID panel with amber/green rating.
Sources: Literature, Radboud University Medical Center, Nijmegen
Early onset or syndromic epilepsy v2.122 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TMEM106B was set to AMBER
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Intellectual disability v3.170 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TMEM106B was set to GREEN
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Early onset or syndromic epilepsy v2.122 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to GREEN
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability v3.170 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to AMBER
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability v3.170 EXOC2 Konstantinos Varvagiannis gene: EXOC2 was added
gene: EXOC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EXOC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC2 were set to 32639540
Phenotypes for gene: EXOC2 were set to Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Penetrance for gene: EXOC2 were set to Complete
Review for gene: EXOC2 was set to AMBER
Added comment: Van Bergen et al (2020 - PMID: 32639540) report on 3 individuals from 2 families, harboring biallelic EXOC2 mutations.

Clinical presentation included DD, ID (severe in 2 subjects from fam1, borderline intellectual functioning in fam2), dysmorphic features and brain abnormalities. Cerebellar anomalies were common to all with a molar tooth sign observed in one (1/3). Other findings limited to subjects from one family included acquired microcephaly, congenital contractures, spastic quadriplegia (each observed 2/3).

Previous investigations were in all cases non-diagnostic. WES identified biallelic EXOC2 mutations in all affected individuals.

EXOC2 encodes an exocyst subunit. The latter is an octameric complex, component of the membrane transport machinery, required for tethering and fusion of vesicles at the plasma membrane. As discussed ,vesicle transport is important for the development of brain and the function of neurons and glia. Exocyst function is also important for delivery of Arl13b to the primary cilium (biallelic ARL13B mutations cause Joubert syndrome 8) and ciliogenesis.

Affected subjects from a broader consanguineous family (fam1) were homozygous for a truncating variant. Fibroblast studies revealed mRNA levels compatible with NMD (further restored in presence of CHX) as well as reduced protein levels. The female belonging to the second non-consanguineous family was found to harbor 2 missense variants in trans configuration.

An exocytosis defect was demonstrated in fibroblasts from individuals belonging to both families. Ciliogenesis appeared to be normal, however Arl13b localization/recruitment to the cilia was reduced compared with control cells with the defect rescued upon exogenous expression of wt EXOC2.

Mutations in other genes encoding components of the exocyst complex have been previously reported in individuals with relevant phenotypes (e.g. EXOC8 in a boy with features of Joubert s. or EXOC4 in nephrotic syndrome).

The authors discuss on the essential role of EXOC2 based on model organism studies (e.g. impaired neuronal membrane traffic, failure of neuronal polarization and neuromuscular junction expansion seen in Drosophila Sec5 (EXOC2) null mutants).
Sources: Literature
Intellectual disability v3.170 CEP120 Konstantinos Varvagiannis gene: CEP120 was added
gene: CEP120 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CEP120 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP120 were set to 27208211
Phenotypes for gene: CEP120 were set to Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300)
Penetrance for gene: CEP120 were set to Complete
Review for gene: CEP120 was set to GREEN
Added comment: Pathogenic CEP120 variants have been reported in recessive ciliopathies, namely Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) and Joubert syndrome 31 (MIM 617761).

The former is associated with a severe/lethal outcome (4 unrelated infants described by Shaheen et al 2015 - PMID: 25361962, 2 fetuses reported by Roosing et al 2016 - PMID: 27208211).

Roosing et al however, also provided details on 4 unrelated subjects with Joubert syndrome diagnosis. All presented with a neurologic phenotype of hypotonia, DD, cognitive impairment and exhibited a molar tooth sign.

As a result, this gene can be considered for inclusion in the ID panel with green rating (>3 individuals/variants, consistent ciliopathy phenotype).
Sources: Literature
Intellectual disability v3.170 CCDC174 Konstantinos Varvagiannis gene: CCDC174 was added
gene: CCDC174 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC174 were set to 26358778
Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816
Penetrance for gene: CCDC174 were set to Complete
Mode of pathogenicity for gene: CCDC174 was set to Other
Review for gene: CCDC174 was set to AMBER
Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816).

Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype.

Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports.
Sources: Literature
Intellectual disability v3.170 ACOX2 Konstantinos Varvagiannis gene: ACOX2 was added
gene: ACOX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ACOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACOX2 were set to 27647924; 27884763; 29287774
Phenotypes for gene: ACOX2 were set to Bile acid synthesis defect, congenital, 6 - 617308
Penetrance for gene: ACOX2 were set to unknown
Review for gene: ACOX2 was set to RED
Added comment: Biallelic pathogenic ACOX2 variants cause Bile acid synthesis defect, congenital, 6 (MIM 617308). Overall the phenotype corresponds to an IEM/peroxisomal disorder.

As per 01-07-2020 there are 3 reports, briefly reviewed :

- Vilarinho et al [2016 - PMID: 27647924] provided details on an 8-year-old boy with ID.
- Monte et al [2017 - PMID: 27884763] described a 16 year old male with sustained elevation of transaminases *without* accompanying neurologic symptomatology (as they comment).
- Ferdinandusse et al [2018 - PMID: 29287774] reported on a girl deceased at the age of few months.

Please consider inclusion in the ID panel with amber/red rating pending further reports.
Sources: Literature
Early onset or syndromic epilepsy v2.122 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Penetrance for gene: ABCA2 were set to Complete
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature
Intellectual disability v3.170 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Penetrance for gene: ABCA2 were set to Complete
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature
Intellectual disability v3.170 HERC2 Konstantinos Varvagiannis edited their review of gene: HERC2: Added comment: Please consider upgrading this gene to green in the current panel based on the following updated review (13-07-2020):

Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.

-----; Changed rating: GREEN; Changed publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030
Early onset or syndromic epilepsy v2.122 HERC2 Konstantinos Varvagiannis gene: HERC2 was added
gene: HERC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HERC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HERC2 were set to 23065719; 23243086; 30902390; 32571899; 27848944; 26077850; 27759030
Phenotypes for gene: HERC2 were set to Mental retardation, autosomal recessive 38 (MIM 615516)
Penetrance for gene: HERC2 were set to Complete
Review for gene: HERC2 was set to GREEN
Added comment: Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.
Sources: Literature
Early onset or syndromic epilepsy v2.122 SEC31A Sarah Leigh gene: SEC31A was added
gene: SEC31A was added to Genetic epilepsy syndromes. Sources: Literature
watchlist tags were added to gene: SEC31A.
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to 30464055
Phenotypes for gene: SEC31A were set to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651
Review for gene: SEC31A was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature
Intellectual disability v3.170 SEC31A Sarah Leigh Classified gene: SEC31A as Amber List (moderate evidence)
Intellectual disability v3.170 SEC31A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Intellectual disability v3.170 SEC31A Sarah Leigh Gene: sec31a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.169 SEC31A Sarah Leigh Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, OMIM #618651 to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651
Intellectual disability v3.168 SBF1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases. The phenotypes vary, but early‐onset microcephaly and moderate‐severe developmental delay were reported in 3 cases (PMID 30039846, 21210780, 20658556).
Intellectual disability v3.168 SBF1 Sarah Leigh Classified gene: SBF1 as Amber List (moderate evidence)
Intellectual disability v3.168 SBF1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in at least 5 unrelated cases.
Intellectual disability v3.168 SBF1 Sarah Leigh Gene: sbf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.167 SBF1 Sarah Leigh reviewed gene: SBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.167 SBF1 Sarah Leigh Tag for-review tag was added to gene: SBF1.
Intellectual disability v3.167 SBF1 Sarah Leigh Phenotypes for gene: SBF1 were changed from Charcot-Marie-Tooth disease, type 4B3, MIM# 615284 to Charcot-Marie-Tooth disease, type 4B3 615284
Intellectual disability v3.166 SARS2 Sarah Leigh edited their review of gene: SARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.166 SARS2 Sarah Leigh Tag for-review tag was added to gene: SARS2.
Intellectual disability v3.166 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Intellectual disability v3.166 SARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 3 unrelated cases. Segregates with the disease.
Intellectual disability v3.166 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.165 SARS2 Sarah Leigh Publications for gene: SARS2 were set to 21255763; 24034276
Intellectual disability v3.164 SARS2 Sarah Leigh Phenotypes for gene: SARS2 were changed from Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845 to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845
Early onset or syndromic epilepsy v2.121 RUSC2 Sarah Leigh edited their review of gene: RUSC2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrelated cases. No functional studies have been reported, although authors of PMID 27612186 suggest that p.R866* results in total loss of function as the sibs biallelic with this variant have a more severe phenotype than the case who is biallelic for p.R1318*, which they conclude results in partial loss of function. Refractory seizures were seen in the sibs with p.R866*.; Changed rating: RED
Early onset or syndromic epilepsy v2.121 RUSC2 Sarah Leigh Phenotypes for gene: RUSC2 were changed from to Mental retardation, autosomal recessive 61 617773
Early onset or syndromic epilepsy v2.120 RUSC2 Sarah Leigh Publications for gene: RUSC2 were set to
Intellectual disability v3.163 RUSC2 Sarah Leigh Classified gene: RUSC2 as Amber List (moderate evidence)
Intellectual disability v3.163 RUSC2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrelated cases. No functional studies have been reported, although authors of PMID 27612186 suggest that p.R866* results in total loss of function as the sibs biallelic with this variant have a more severe phenotype than the case who is biallelic for p.R1318*, which they conclude results in partial loss of function.
Intellectual disability v3.163 RUSC2 Sarah Leigh Gene: rusc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.162 RUSC2 Sarah Leigh Phenotypes for gene: RUSC2 were changed from Mental retardation, autosomal recessive 61, MIM# 617773 to Mental retardation, autosomal recessive 61 617773
Fetal anomalies v1.74 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Hereditary neuropathy or pain disorder v1.6 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Intellectual disability v3.161 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
DDG2P v2.9 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Fetal anomalies v1.74 SLC12A6 Sarah Leigh commented on gene: SLC12A6
Hereditary neuropathy or pain disorder v1.6 SLC12A6 Sarah Leigh commented on gene: SLC12A6
Intellectual disability v3.161 SLC12A6 Sarah Leigh commented on gene: SLC12A6
DDG2P v2.9 SLC12A6 Sarah Leigh Deleted their comment
DDG2P v2.9 SLC12A6 Sarah Leigh commented on gene: SLC12A6: Associated with Agenesis of the corpus callosum with peripheral neuropathy 218000 in OMIM and as confirmed Gen2Phen gene. At least 10 biallelic variants were reported in at least 10 unrelated cases. 9/10 of these variants was terminating (PMID 12368912, 16606917, 17893295). Three de novo heterozygous missense variants have been identified in four unrelated cases with a milder phenotype of early- onset progressive Charcot- Marie-tooth disease (CMT) with or without spasticity (intermediate CMT)(PMID 31439721, 27485015). The authors of PMID 31439721 suggest that "autosomal- dominant inheritance of SLC12A6 variants also needs to be considered in patients with early- onset neuropathies". Furthermore, it will be important to understand the functional differences between the variants, as PMID 27485015 reported variant - p.Thr991Ala, resulted in increased potassium influx in Xenopus oocytes (gain-of-function), while the other missense variants identified so far had a loss-of-function effect in varying degrees (PMID 31439721).
Fetal anomalies v1.74 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to
Intellectual disability v3.161 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to
Hereditary neuropathy or pain disorder v1.6 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 12368912
Hereditary neuropathy v1.374 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 12368912; 31439721; 27485015; 16606917; 17893295
DDG2P v2.9 SLC12A6 Sarah Leigh Added comment: Comment on publications: 12368912;31439721;27485015;16606917;17893295;21628467
DDG2P v2.9 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 17893295; 16606917; 21628467; 12368912
Hereditary neuropathy v1.373 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 12368912; 31439721; 27485015; 12368912; 16606917; 17893295
Hereditary neuropathy v1.372 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 12368912; 31439721; 27485015
Fetal anomalies v1.73 SLC12A6 Sarah Leigh Tag for-review tag was added to gene: SLC12A6.
Hereditary neuropathy or pain disorder v1.5 SLC12A6 Sarah Leigh Tag for-review tag was added to gene: SLC12A6.
Intellectual disability v3.160 SLC12A6 Sarah Leigh Tag for-review tag was added to gene: SLC12A6.
Hereditary neuropathy v1.371 SLC12A6 Sarah Leigh changed review comment from: For-review tag has been added as it mabe appropriate for the MOI to be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.; to: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Hereditary neuropathy v1.371 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it mabe appropriate for the MOI to be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Hereditary neuropathy v1.371 SLC12A6 Sarah Leigh Tag for-review tag was added to gene: SLC12A6.
Hereditary neuropathy v1.371 SLC12A6 Sarah Leigh reviewed gene: SLC12A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 12368912, 16606917, 17893295; Phenotypes: Agenesis of the corpus callosum with peripheral neuropathy 218000; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.13 FDXR Ivone Leong Phenotypes for gene: FDXR were changed from Auditory neuropathy and optic atrophy, MIM#617717 to Auditory neuropathy and optic atrophy, 617717
Optic neuropathy v2.12 FDXR Ivone Leong Publications for gene: FDXR were set to 30250212; 28965846
Optic neuropathy v2.11 MECR Ivone Leong Classified gene: MECR as Amber List (moderate evidence)
Optic neuropathy v2.11 MECR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark and an additional Green review from Sara Martins. MECR is associated with a relevant phenotype in OMIM and probably associated with a relevant phenotype in Gene2Phenotype. There is enough evidence for this gene to be Green. Currently, it is rated Amber and will be promoted to Green status at the next major review.
Optic neuropathy v2.11 MECR Ivone Leong Gene: mecr has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.10 MECR Ivone Leong Tag for-review tag was added to gene: MECR.
Optic neuropathy v2.10 MECR Ivone Leong Phenotypes for gene: MECR were changed from Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities to Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, 617282
Optic neuropathy v2.9 NBAS Ivone Leong Classified gene: NBAS as Amber List (moderate evidence)
Optic neuropathy v2.9 NBAS Ivone Leong Gene: nbas has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.8 NBAS Ivone Leong Classified gene: NBAS as No list
Optic neuropathy v2.8 NBAS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. NBAS is associated with an appropriate phenotype in OMIM and probably associated with an appropriate phenotype in Gene2Phenotype.

PMID: 31015584 describes another unrelated case where patients has variant in NBAS and also had optic atrophy.

PMID: 31761904 is a study that looked at defining the spectrum of phenotypes related to NBAS. There are > 3 cases of individuals with variants in NBAS who have optic atropy.

Therefore, there is enough evidence for this gene to be Green. This gene will be made Green at the next major review.
Optic neuropathy v2.8 NBAS Ivone Leong Gene: nbas has been removed from the panel.
Optic neuropathy v2.7 NBAS Ivone Leong Tag for-review tag was added to gene: NBAS.
Optic neuropathy v2.7 NBAS Ivone Leong Publications for gene: NBAS were set to 20577004; 26286438
Hereditary neuropathy v1.371 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 12368912; 31439721
Optic neuropathy v2.6 NBAS Ivone Leong Phenotypes for gene: NBAS were changed from Short stature, optic nerve atrophy, and Pelger-Huet anomaly to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, 614800
Optic neuropathy v2.5 UCHL1 Ivone Leong Classified gene: UCHL1 as Amber List (moderate evidence)
Optic neuropathy v2.5 UCHL1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Based on provided evidence there is enough evidence to support a gene-disease association and Green status. However, this gene is currently rated Amber and tagged with "for-review" until the next major review at which point this gene should be made Green.
Optic neuropathy v2.5 UCHL1 Ivone Leong Gene: uchl1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.4 UCHL1 Ivone Leong Tag for-review tag was added to gene: UCHL1.
Optic neuropathy v2.4 UCHL1 Ivone Leong Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive (MIM#615491) to Spastic paraplegia 79, autosomal recessive, 615491
Short QT syndrome v2.3 CACNA1C Ivone Leong Tag for-review tag was added to gene: CACNA1C.
Arthrogryposis v3.11 TRIP4 Zornitza Stark reviewed gene: TRIP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26924529; Phenotypes: Spinal muscular atrophy with congenital bone fractures 1, MIM# 616866; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Arthrogryposis v3.11 TBCD Zornitza Stark reviewed gene: TBCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27666370, 27666374; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, MIM# 617193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.11 SYNE1 Zornitza Stark reviewed gene: SYNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27782104; Phenotypes: Distal arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Arthrogryposis v3.11 SCN4A Zornitza Stark reviewed gene: SCN4A: Rating: RED; Mode of pathogenicity: None; Publications: 26700687; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.11 NUP88 Zornitza Stark gene: NUP88 was added
gene: NUP88 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: NUP88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP88 were set to 30543681
Phenotypes for gene: NUP88 were set to Fetal akinesia deformation sequence 4, MIM# 618393
Review for gene: NUP88 was set to GREEN
gene: NUP88 was marked as current diagnostic
Added comment: Two unrelated families, functional data on the variants support pathogenicity as does a zebrafish model.
Sources: Expert list
Arthrogryposis v3.11 MYL1 Zornitza Stark reviewed gene: MYL1: Rating: RED; Mode of pathogenicity: None; Publications: 30215711; Phenotypes: Myopathy, congenital, with fast-twitch (type II) fiber atrophy, MIM# 618414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.11 MED12 Zornitza Stark gene: MED12 was added
gene: MED12 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: MED12 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MED12 were set to 20301719
Phenotypes for gene: MED12 were set to MED12-related disorders
Review for gene: MED12 was set to GREEN
gene: MED12 was marked as current diagnostic
Added comment: Contractures are a recognised feature.
Sources: Expert list
Arthrogryposis v3.11 ISLR2 Zornitza Stark gene: ISLR2 was added
gene: ISLR2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: ISLR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISLR2 were set to 30483960
Phenotypes for gene: ISLR2 were set to hydrocephalus; arthrogryposis
Review for gene: ISLR2 was set to AMBER
Added comment: Single consanguineous family with hydrocephalus and arthrogryposis and homozygous truncating variant, mouse model has hydrocephalus
Sources: Expert list
Arthrogryposis v3.11 FLNC Zornitza Stark reviewed gene: FLNC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29858533; Phenotypes: Cardiomyopathy, familial restrictive 5 617047, Myopathy, distal, 4 614065, Myopathy, myofibrillar, 5 609524; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Arthrogryposis v3.11 FLNA Zornitza Stark gene: FLNA was added
gene: FLNA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: FLNA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: FLNA were set to 26804200; 30561107; 20301567
Phenotypes for gene: FLNA were set to FLNA-related disorders; Otopalatodigital syndrome, type I 311300; Otopalatodigital syndrome, type II 304120; Terminal osseous dysplasia 300244
Review for gene: FLNA was set to GREEN
Added comment: Contractures are part of the phenotype of some FLNA-related disorders, in particular otopalatodigital syndrome and terminal osseous dysplasia.
Sources: Expert list
Arthrogryposis v3.11 ERCC5 Zornitza Stark changed review comment from: Single family reported with 5 affected fetuses and severe COFS including arthrogryposis.; to: A family reported with 5 affected fetuses and severe COFS including arthrogryposis in PMID:24700531. Further two included in a recent review of severe neonatal presentations of nucleotide excision-repair disorders (PMID:32557569).
Arthrogryposis v3.11 ERCC5 Zornitza Stark edited their review of gene: ERCC5: Changed rating: GREEN; Changed publications: 24700531, 32557569
Arthrogryposis v3.11 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 24700531; Phenotypes: Cerebrooculofacioskeletal syndrome 3, MIM# 616570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.11 EBP Zornitza Stark gene: EBP was added
gene: EBP was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: EBP was set to Other
Publications for gene: EBP were set to 21634086; 24704792
Phenotypes for gene: EBP were set to Chondrodysplasia punctata, X-linked dominant, MIM# 302960
Review for gene: EBP was set to GREEN
gene: EBP was marked as current diagnostic
Added comment: XLD. Contractures are a reported feature.
Sources: Expert list
Atypical haemolytic uraemic syndrome v2.7 ADAMTS13 Eleanor Williams Tag for-review tag was added to gene: ADAMTS13.
Renal ciliopathies v1.25 KIF14 Eleanor Williams Tag watchlist tag was added to gene: KIF14.
Renal ciliopathies v1.25 KIF14 Eleanor Williams commented on gene: KIF14
Intellectual disability v3.160 RIC1 Sarah Leigh Tag founder-effect tag was added to gene: RIC1.
Non-CF bronchiectasis v1.22 DNAH5 Zerin Hyder reviewed gene: DNAH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 18037990, 11788826; Phenotypes: Primary Ciliary Dyskinesia, Ciliary dyskinesia, primary, 3, with or without situs inversus, 608644, situs inversus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.25 ICK Eleanor Williams Tag for-review tag was added to gene: ICK.
Renal ciliopathies v1.25 ICK Eleanor Williams Tag watchlist tag was added to gene: ICK.
Renal ciliopathies v1.25 NEK1 Eleanor Williams Classified gene: NEK1 as Amber List (moderate evidence)
Renal ciliopathies v1.25 NEK1 Eleanor Williams Added comment: Comment on list classification: After discussion with the Genomics England clinical team it was decided to rate this gene amber as although there is a renal phenotype there is a more striking skeletal component and having this gene green may create extra noise in renal-only presentations.
Renal ciliopathies v1.25 NEK1 Eleanor Williams Gene: nek1 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.24 NEK1 Eleanor Williams Tag watchlist tag was added to gene: NEK1.
Renal ciliopathies v1.24 NEK1 Eleanor Williams Publications for gene: NEK1 were set to
Renal ciliopathies v1.23 NEK1 Eleanor Williams edited their review of gene: NEK1: Changed publications: 21211617, 22499340, 25492405, 28123176; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.23 NEK1 Eleanor Williams edited their review of gene: NEK1: Changed rating: AMBER
Early onset or syndromic epilepsy v2.119 OTUD7A Sarah Leigh commented on gene: OTUD7A: Review by Zornitza Stark on Intellectual disability panel https://panelapp.genomicsengland.co.uk/panels/285/: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.
Early onset or syndromic epilepsy v2.119 OTUD7A Sarah Leigh gene: OTUD7A was added
gene: OTUD7A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, intellectual disability
Review for gene: OTUD7A was set to RED
Added comment: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Sources: Literature
Renal ciliopathies v1.23 ICK Eleanor Williams edited their review of gene: ICK: Added comment: After discussion with the Genomics England clinical team it was decided this gene should be downgraded from green to amber at the next review.

Evidence for a renal phenotype is borderline, with some evidence for an absence of a phenotype.

PMID: 19185282 - 2 Amish families () have the same variant in ICK and 3 infants from these families showed cystically dilated tubules in both the medulla and the cortex of the kidney. 
PMID: 27069622 - 1 family is reported where a foetal scan showed large and hyperechogenic kidneys. 
PMID: 27466187 - reports a newborn with short rib polydactyly syndrome and a variant in ICK, but no renal phenotype. Two mouse knockout models (PMID: 24853502 and 24797473) also do not show a kidney phenotype.; Changed rating: AMBER; Changed publications: 19185282, 27069622, 27466187, 24853502, 24797473
Renal ciliopathies v1.23 HNF1B Eleanor Williams commented on gene: HNF1B
Familial hypercholesterolaemia v1.27 LDLR Sarah Leigh Publications for gene: LDLR were set to PMID: 23433573; 25414277
Inherited white matter disorders v1.78 GALNT2 Sarah Leigh Classified gene: GALNT2 as Green List (high evidence)
Inherited white matter disorders v1.78 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Green List (High Evidence).
Intellectual disability v3.160 GALNT2 Sarah Leigh Classified gene: GALNT2 as Amber List (moderate evidence)
Intellectual disability v3.160 GALNT2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.160 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Classified gene: GALNT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.159 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Intellectual disability. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Inherited white matter disorders v1.77 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Inherited white matter disorders. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Early onset or syndromic epilepsy v2.117 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Congenital disorders of glycosylation v2.14 GALNT2 Sarah Leigh Deleted their comment
Congenital disorders of glycosylation v2.14 GALNT2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least unrelated cases, together with mouse and rat models (PMID 27508872;32293671).; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.11 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Early onset or syndromic epilepsy v2.115 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Severe microcephaly v2.11 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Severe microcephaly v2.11 ADARB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.11 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.158 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Intellectual disability v3.158 ADARB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.158 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.157 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Likely inborn error of metabolism v2.15 ALG14 Sarah Leigh edited their review of gene: ALG14: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Likely inborn error of metabolism v2.15 ALG14 Sarah Leigh Tag for-review tag was added to gene: ALG14.
Undiagnosed metabolic disorders v1.418 ALG14 Sarah Leigh edited their review of gene: ALG14: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Undiagnosed metabolic disorders v1.418 ALG14 Sarah Leigh Tag for-review tag was added to gene: ALG14.
Likely inborn error of metabolism v2.15 ALG14 Sarah Leigh Publications for gene: ALG14 were set to 27604308; 23404334
Undiagnosed metabolic disorders v1.418 ALG14 Sarah Leigh Publications for gene: ALG14 were set to 27604308
Likely inborn error of metabolism v2.14 ALG14 Sarah Leigh Classified gene: ALG14 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.14 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Likely inborn error of metabolism v2.14 ALG14 Sarah Leigh Gene: alg14 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.417 ALG14 Sarah Leigh Classified gene: ALG14 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.417 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Undiagnosed metabolic disorders v1.417 ALG14 Sarah Leigh Gene: alg14 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh changed review comment from: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature; to: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature
Congenital disorders of glycosylation v2.14 ALG14 Sarah Leigh commented on gene: ALG14: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital disorders of glycosylation v2.14 ALG14 Sarah Leigh Classified gene: ALG14 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.14 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Congenital disorders of glycosylation v2.14 ALG14 Sarah Leigh Gene: alg14 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v2.13 ALG14 Sarah Leigh Publications for gene: ALG14 were set to 27604308; 23404334
Congenital disorders of glycosylation v2.12 ALG14 Sarah Leigh Tag for-review tag was added to gene: ALG14.
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Classified gene: ALG14 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Gene: alg14 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.114 ALG14 Sarah Leigh gene: ALG14 was added
gene: ALG14 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: ALG14.
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 28733338; 23404334; 30221345
Phenotypes for gene: ALG14 were set to Congenital myasthenic syndrome; ?Myasthenic syndrome, congenital, 15, without tubular aggregates, 616227
Review for gene: ALG14 was set to AMBER
Added comment: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature
Severe microcephaly v2.10 ADARB1 Arina Puzriakova gene: ADARB1 was added
gene: ADARB1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Review for gene: ADARB1 was set to GREEN
Added comment: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Affected individuals were microcephalic at birth or developed postnatal microcephaly ranging from -3.6 to -4.0 SD. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545).

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature
Congenital myaesthenic syndrome v2.5 ALG14 Sarah Leigh Publications for gene: ALG14 were set to 28733338; 23404334
Early onset or syndromic epilepsy v2.113 ADARB1 Arina Puzriakova gene: ADARB1 was added
gene: ADARB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Review for gene: ADARB1 was set to GREEN
Added comment: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures, which were intractable in three of the individuals. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature
Intellectual disability v3.157 ALG14 Sarah Leigh changed review comment from: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants.; to: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants. This will be reviewed as more cases are reported.
Intellectual disability v3.157 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.10 TTC5 Sarah Leigh commented on gene: TTC5: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.10 TTC5 Sarah Leigh commented on gene: TTC5: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.10 TTC5 Sarah Leigh Classified gene: TTC5 as Amber List (moderate evidence)
Severe microcephaly v2.10 TTC5 Sarah Leigh Gene: ttc5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.9 TTC5 Sarah Leigh gene: TTC5 was added
gene: TTC5 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: TTC5.
Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC5 were set to 29302074; 32439809
Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Review for gene: TTC5 was set to GREEN
Added comment: Not associated with a relevant phenotype in OMIM and as probable Gen2Phen gene for TTC5-associated neurodevelopmental disorder. At least 7 cases with biallelic variants.
Sources: Literature
COVID-19 research v1.59 KIR2DL2 Eleanor Williams commented on gene: KIR2DL2
COVID-19 research v1.59 CCL3L1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: CCL3L1.
COVID-19 research v1.59 CCL3L1 Eleanor Williams commented on gene: CCL3L1
Hyperthyroidism v2.6 TRU-TCA1-1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: TRU-TCA1-1.
Hyperthyroidism v2.6 TRU-TCA1-1 Eleanor Williams commented on gene: TRU-TCA1-1
COVID-19 research v1.59 TRBC1 Eleanor Williams commented on gene: TRBC1
Hereditary spastic paraplegia v1.215 SPG41 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG41.
Hereditary spastic paraplegia v1.215 SPG38 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG38.
Hereditary spastic paraplegia v1.215 SPG37 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG37.
Hereditary spastic paraplegia v1.215 SPG36 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG36.
Hereditary spastic paraplegia v1.215 SPG34 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG34.
Hereditary spastic paraplegia v1.215 SPG32 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG32.
Hereditary spastic paraplegia v1.215 SPG29 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG29.
Hereditary spastic paraplegia v1.215 SPG27 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG27.
Hereditary spastic paraplegia v1.215 SPG25 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG25.
Hereditary spastic paraplegia v1.215 SPG24 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG24.
Hereditary spastic paraplegia v1.215 SPG23 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG23.
Hereditary spastic paraplegia v1.215 SPG19 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG19.
Hereditary spastic paraplegia v1.215 SPG16 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG16.
Hereditary spastic paraplegia v1.215 SPG14 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: SPG14.
Inherited non-medullary thyroid cancer v1.4 PTCSC1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: PTCSC1.
Inherited non-medullary thyroid cancer v1.4 PTCSC1 Eleanor Williams commented on gene: PTCSC1
Pancreatitis v2.4 PRSS2 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: PRSS2.
Pancreatitis v2.4 PRSS2 Eleanor Williams commented on gene: PRSS2
Optic neuropathy v2.3 OPA8 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: OPA8.
Optic neuropathy v2.3 OPA6 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: OPA6.
Optic neuropathy v2.3 OPA5 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: OPA5.
Optic neuropathy v2.3 OPA4 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: OPA4.
Optic neuropathy v2.3 OPA2 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: OPA2.
Ocular and oculo-cutaneous albinism v1.21 OCA5 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: OCA5.
Cerebral vascular malformations v2.4 MYMY3 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: MYMY3.
Cerebral vascular malformations v2.4 MYMY1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: MYMY1.
COVID-19 research v1.59 MIR155 Eleanor Williams commented on gene: MIR155
Bilateral congenital or childhood onset cataracts v2.6 MAFIP Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: MAFIP.
Bilateral congenital or childhood onset cataracts v2.6 MAFIP Eleanor Williams commented on gene: MAFIP
Paroxysmal central nervous system disorders v1.3 KCNJ18 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: KCNJ18.
Paroxysmal central nervous system disorders v1.3 KCNJ18 Eleanor Williams commented on gene: KCNJ18
Skeletal Muscle Channelopathies v1.21 KCNJ18 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: KCNJ18.
Skeletal Muscle Channelopathies v1.21 KCNJ18 Eleanor Williams commented on gene: KCNJ18
Haematological malignancies cancer susceptibility v2.3 HPLH1 Eleanor Williams Tag locus-type-phenotype-only tag was added to gene: HPLH1.
Tag ensembl_ids_known_missing tag was added to gene: HPLH1.
Familial Neural Tube Defects v1.6 HPE1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: HPE1.
Clefting v2.3 FSHMD1A Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: FSHMD1A.
Retinal disorders v2.14 EVR3 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: EVR3.
Deafness and congenital structural abnormalities v1.17 DWS Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: DWS.
Hereditary ataxia with onset in adulthood v2.8 ATXN8 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: ATXN8.
Hereditary ataxia with onset in adulthood v2.8 ATXN8 Eleanor Williams commented on gene: ATXN8
Adult onset neurodegenerative disorder v2.4 ATXN8 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: ATXN8.
Adult onset neurodegenerative disorder v2.4 ATXN8 Eleanor Williams commented on gene: ATXN8
Hereditary ataxia v1.205 ATXN8 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: ATXN8.
Hereditary ataxia v1.205 ATXN8 Eleanor Williams commented on gene: ATXN8
Ataxia and cerebellar anomalies - narrow panel v2.6 ATXN8 Eleanor Williams commented on gene: ATXN8
Ataxia and cerebellar anomalies - narrow panel v2.6 ATXN8 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: ATXN8.
Rare multisystem ciliopathy disorders v1.125 ATD Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: ATD.
Cerebral vascular malformations v2.4 ANIB1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: ANIB1.
Glycogen storage disease v1.4 PYGM Sarah Leigh Tag watchlist tag was added to gene: PYGM.
Tag for-review tag was added to gene: PYGM.
Glycogen storage disease v1.4 PYGM Sarah Leigh commented on gene: PYGM
Additional findings health related - adults v0.22 Eleanor Williams Panel name changed from Additional findings health related -  adults to Additional findings health related - adults
Hereditary neuropathy v1.370 SLC12A6 Sarah Leigh Publications for gene: SLC12A6 were set to 12368912
Early onset or syndromic epilepsy v2.113 SLC5A6 Sarah Leigh commented on gene: SLC5A6: Watchlist tag was added to take account of the potential therapeutic options of this cause of seizures.
Early onset or syndromic epilepsy v2.113 SLC5A6 Sarah Leigh Tag watchlist tag was added to gene: SLC5A6.
Intellectual disability v3.157 SETD1A Sarah Leigh reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.157 FEM1B Arina Puzriakova edited their review of gene: FEM1B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.157 FEM1B Arina Puzriakova changed review comment from: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals.

No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.; to: Lecoquierre et al. (2019) (PMID: 31036916) conducted a large candidate gene discovery studying and identified a de novo missense variant (p.Arg126Gln) in a patient with syndromic global developmental delay. Recurrence of the same variant was highlighted in an individual from the DDD study, and the another from GeneMatcher. It is said that the three patients share a similar phenotype; however, any further details are limited and it is not possible to ascertain whether the additional patients refer to different individuals. No function analysis was undertaken to validate the implication of FEM1B.

Gene not associated with any phenotype on OMIM or G2P.
Bilateral congenital or childhood onset cataracts v2.6 NACC1 Zornitza Stark gene: NACC1 was added
gene: NACC1 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: NACC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NACC1 were set to 28132692
Phenotypes for gene: NACC1 were set to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination (MIM# 617393)
Review for gene: NACC1 was set to GREEN
gene: NACC1 was marked as current diagnostic
Added comment: 7 unrelated individuals with recurrent de novo heterozygous missense variant c.892C>T p.(Arg298Trp). 5 out of 7 had bilateral cataracts.
Sources: Expert list
Intellectual disability v3.157 SETD1A Sarah Leigh Publications for gene: SETD1A were set to 28135719; 26974950
Bilateral congenital or childhood onset cataracts v2.6 NUP188 Zornitza Stark gene: NUP188 was added
gene: NUP188 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 28726809; 32275884
Phenotypes for gene: NUP188 were set to microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Review for gene: NUP188 was set to GREEN
gene: NUP188 was marked as current diagnostic
Added comment: 8 unrelated individuals reported with bi-allelic variants and a neurodevelopmental phenotype with cataracts.
Sources: Expert list
Intellectual disability v3.156 GNAI2 Arina Puzriakova reviewed gene: GNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31036916, 27787898; Phenotypes: Syndromic developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v2.6 PANK4 Zornitza Stark gene: PANK4 was added
gene: PANK4 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: PANK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PANK4 were set to 30585370
Phenotypes for gene: PANK4 were set to Congenital posterior cataract
Review for gene: PANK4 was set to AMBER
Added comment: Variant segregated with cataract in single 4-generation family, functional data including mouse model.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 PIK3C2A Zornitza Stark reviewed gene: PIK3C2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31034465; Phenotypes: Oculoskeletodental syndrome, MIM# 618440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.113 PTEN Sarah Leigh reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.113 PTEN Sarah Leigh Tag mosaicism was removed from gene: PTEN.
Tag somatic was removed from gene: PTEN.
Tag for-review tag was added to gene: PTEN.
Bilateral congenital or childhood onset cataracts v2.6 PISD Zornitza Stark gene: PISD was added
gene: PISD was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PISD were set to 31263216; 30858161
Phenotypes for gene: PISD were set to Intellectual disability; cataracts; retinal degeneration; microcephaly; deafness; short stature; white matter abnormalities
Review for gene: PISD was set to GREEN
gene: PISD was marked as current diagnostic
Added comment: 4 individuals in 2 unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature (Liberfarb syndrome). Affected individuals shared a homozygous 10-bp deletion immediately upstream of the last exon of the PISD gene. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts.

1 family with 2 sisters with congenital cataracts, short stature, and white matter changes identified compound heterozygous variants in the PISD gene. Decreased conversion of phosphatidylserine to PE in patient fibroblasts is consistent with impaired phosphatidylserine decarboxylase (PISD) enzyme activity.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 INTS1 Zornitza Stark gene: INTS1 was added
gene: INTS1 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: INTS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS1 were set to 28542170; 30622326; 31428919
Phenotypes for gene: INTS1 were set to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, MIM# 618571
Review for gene: INTS1 was set to GREEN
gene: INTS1 was marked as current diagnostic
Added comment: At least 6 unrelated families reported; cataract is a consistent feature, onset in infancy/early childhood.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 GALM Zornitza Stark gene: GALM was added
gene: GALM was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to 30451973; 30910422
Phenotypes for gene: GALM were set to type IV galactosaemia
Review for gene: GALM was set to AMBER
Added comment: Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). This is therefore type IV galactosaemia. In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. Loss-of-function mechanism. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973) In vitro expression assay and an enzyme activity assay of 67 GALM variants, taken from ExAc database (missense, nonsense, frameshift and splice). 30 variants concluded to be pathogenic due to no protein expression or faint expression. 5 variants with mildly lower levels were determined as likely pathogenic. All concluded to be loss-of-function mechanism. Incidence of galactosaemia by GALM deficiency is comparable to that of other galactosaemias. Carrier frequency and incidence was estimated for different populations. (Iwasawa, S. et al. (2019); PMID: 30910422)

Note only two of the reported individuals had cataracts.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 ANAPC1 Zornitza Stark gene: ANAPC1 was added
gene: ANAPC1 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM 618625
Review for gene: ANAPC1 was set to GREEN
gene: ANAPC1 was marked as current diagnostic
Added comment: Rothmund-Thomson syndrome type 1 is associated with juvenile cataracts. Ajeawung et al (PMID 31303264) described 10 individuals from 7 unrelated families with biallelic ANAPC1 variants, whom all had bilateral juvenile cataracts.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 GEMIN4 Zornitza Stark reviewed gene: GEMIN4: Rating: AMBER; Mode of pathogenicity: None; Publications: 25558065, 27878435; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, 617913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.6 GFER Zornitza Stark reviewed gene: GFER: Rating: GREEN; Mode of pathogenicity: None; Publications: 19409522, 25269795, 28155230; Phenotypes: Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay MIM#613076; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.4 GGPS1 Zornitza Stark gene: GGPS1 was added
gene: GGPS1 was added to Congenital muscular dystrophy. Sources: Literature
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy; Deafness; Ovarian insufficiency
Review for gene: GGPS1 was set to GREEN
gene: GGPS1 was marked as current diagnostic
Added comment: 11 individuals from 6 unrelated families reported. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. Knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality.
Sources: Literature
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh commented on gene: NRROS: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.112 NRROS Sarah Leigh gene: NRROS was added
gene: NRROS was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: NRROS.
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075; 28459434
Phenotypes for gene: NRROS were set to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Review for gene: NRROS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Sources: Literature
Intellectual disability v3.156 NRROS Sarah Leigh Phenotypes for gene: NRROS were changed from neurodegeneration; intracranial calcification; epilepsy to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Intellectual disability v3.155 NRROS Sarah Leigh Deleted their comment
Intellectual disability v3.155 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Intellectual disability v3.155 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.155 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.154 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Intellectual disability v3.154 NRROS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Intellectual disability v3.154 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.154 NRROS Sarah Leigh Publications for gene: NRROS were set to 32100099; 32197075
Intellectual disability v3.153 NRROS Sarah Leigh reviewed gene: NRROS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.153 FEM1B Arina Puzriakova reviewed gene: FEM1B: Rating: RED; Mode of pathogenicity: None; Publications: 31036916; Phenotypes: Global developmental delay; Mode of inheritance: None
Intellectual disability v3.153 NOVA2 Sarah Leigh Tag for-review tag was added to gene: NOVA2.
Intellectual disability v3.153 NOVA2 Sarah Leigh Deleted their comment
Intellectual disability v3.153 NOVA2 Sarah Leigh edited their review of gene: NOVA2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.153 NOVA2 Sarah Leigh Classified gene: NOVA2 as Amber List (moderate evidence)
Intellectual disability v3.153 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.153 NOVA2 Sarah Leigh Gene: nova2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.152 NOVA2 Sarah Leigh Classified gene: NOVA2 as Amber List (moderate evidence)
Intellectual disability v3.152 NOVA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073).
Intellectual disability v3.152 NOVA2 Sarah Leigh Gene: nova2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.151 NOVA2 Sarah Leigh Phenotypes for gene: NOVA2 were changed from Intellectual disability; autism; hypotonia; spasticity; ataxia to Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities 618859
Intellectual disability v3.150 CDK19 Sarah Leigh Tag for-review tag was added to gene: CDK19.
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh edited their review of gene: CDK19: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Sources: Literature; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417). PMID 20563892 reports a de novo pericentric inversion in chromosome 6 with breakpoints in 6p12.1 and 6q21 reported in a female patient with microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation. Supporting in vitro and drosophila model data also included.
Sources: Literature
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from to Epileptic encephalopathy, early infantile 87 618916
Early onset or syndromic epilepsy v2.110 CDK19 Sarah Leigh Publications for gene: CDK19 were set to
Intellectual disability v3.150 CDK19 Sarah Leigh Classified gene: CDK19 as Amber List (moderate evidence)
Intellectual disability v3.150 CDK19 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Intellectual disability v3.150 CDK19 Sarah Leigh Gene: cdk19 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.109 CDK19 Sarah Leigh Classified gene: CDK19 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.109 CDK19 Sarah Leigh Gene: cdk19 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.108 CDK19 Sarah Leigh gene: CDK19 was added
gene: CDK19 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CDK19.
Mode of inheritance for gene: CDK19 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: CDK19 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Sources: Literature
Intellectual disability v3.149 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation to Epileptic encephalopathy, early infantile, 87 618916
Intellectual disability v3.148 CDK19 Sarah Leigh Publications for gene: CDK19 were set to 20563892
Intellectual disability v3.148 CDK19 Sarah Leigh Mode of inheritance for gene: CDK19 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.147 WIPI2 Sarah Leigh Classified gene: WIPI2 as Red List (low evidence)
Intellectual disability v3.147 WIPI2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 homozygous variant was reported in 4 members of a consanguineous family.
Intellectual disability v3.147 WIPI2 Sarah Leigh Gene: wipi2 has been classified as Red List (Low Evidence).
Intellectual disability v3.146 WIPI2 Sarah Leigh Phenotypes for gene: WIPI2 were changed from Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 to ?Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Intellectual disability v3.145 GSX2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases, together with supportive functional studies (PMID 31412107).
Intellectual disability v3.145 GSX2 Sarah Leigh Classified gene: GSX2 as Amber List (moderate evidence)
Intellectual disability v3.145 GSX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrealated cases.
Intellectual disability v3.145 GSX2 Sarah Leigh Gene: gsx2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.144 YARS Sarah Leigh changed review comment from: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.; to: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level. He speaks and understands English and Polish.
Renal ciliopathies v1.23 DHCR7 Eleanor Williams Tag for-review tag was added to gene: DHCR7.
Renal ciliopathies v1.23 CENPF Eleanor Williams Tag for-review tag was added to gene: CENPF.
Renal ciliopathies v1.23 ALMS1 Eleanor Williams Tag for-review tag was added to gene: ALMS1.
Renal ciliopathies v1.23 DHCR7 Eleanor Williams reviewed gene: DHCR7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Renal ciliopathies v1.23 CENPF Eleanor Williams reviewed gene: CENPF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Renal ciliopathies v1.23 ALMS1 Eleanor Williams reviewed gene: ALMS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.6 EED Zornitza Stark reviewed gene: EED: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cohen-Gibson syndrome, MIM# 617561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v2.6 CTDP1 Zornitza Stark changed review comment from: Although it is a founder variant, the number of families reported is large and the population is not geographically restricted, i.e. is present in the UK.; to: Although it is a founder variant, the number of families reported is large and the population is not geographically restricted, i.e. is present in the UK. The gene is Green on the neuropathy and ID panels.
Bilateral congenital or childhood onset cataracts v2.6 CTDP1 Zornitza Stark reviewed gene: CTDP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 14517542, 24690360; Phenotypes: Congenital cataracts, facial dysmorphism, and neuropathy, MIM# 604168; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.6 COG4 Zornitza Stark gene: COG4 was added
gene: COG4 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: COG4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COG4 were set to 31949312; 30290151
Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM #618150
Review for gene: COG4 was set to GREEN
gene: COG4 was marked as current diagnostic
Added comment: Saul-Wilson syndrome (AD): 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like)
All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). Please note bi-allelic variants cause CDG.
Sources: Expert list
Likely inborn error of metabolism v2.13 DPYS Eleanor Williams Publications for gene: DPYS were set to 27604308
Primary lymphoedema v2.4 CHD7 Ivone Leong reviewed gene: CHD7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.6 ABHD12 Zornitza Stark reviewed gene: ABHD12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32077159, 29571850, 28448692, 24697911; Phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, MIM# 612674; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Bilateral congenital or childhood onset cataracts v2.6 PLOD3 Zornitza Stark gene: PLOD3 was added
gene: PLOD3 was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD3 were set to 18834968; 30463024; 31129566
Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency, MIM#612394
Review for gene: PLOD3 was set to GREEN
gene: PLOD3 was marked as current diagnostic
Added comment: Complex phenotype that includes cataracts in 3/5 described unrelated families.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 POLG Zornitza Stark edited their review of gene: POLG: Set current diagnostic: yes
Bilateral congenital or childhood onset cataracts v2.6 POLG Zornitza Stark gene: POLG was added
gene: POLG was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: POLG was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLG were set to 20301791; 29358615; 22405928
Phenotypes for gene: POLG were set to POLG-related disorders
Review for gene: POLG was set to GREEN
Added comment: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants. Cataracts have been described as congenital/preceding other clinical manifestations.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 SLC16A12 Zornitza Stark reviewed gene: SLC16A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 29088427; Phenotypes: Cataract 47, juvenile, with microcornea, MIM# 612018; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v2.6 TKFC Zornitza Stark gene: TKFC was added
gene: TKFC was added to Cataracts. Sources: Expert list
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446
Phenotypes for gene: TKFC were set to Developmental delay; cataracts; liver dysfunction
Review for gene: TKFC was set to AMBER
Added comment: Two unrelated individuals reported.
Sources: Expert list
Hereditary neuropathy or pain disorder v1.5 YARS Sarah Leigh Tag new-gene-name tag was added to gene: YARS.
Hereditary neuropathy or pain disorder v1.5 YARS Sarah Leigh commented on gene: YARS
Hereditary neuropathy v1.369 YARS Sarah Leigh commented on gene: YARS
Hereditary neuropathy v1.369 YARS Sarah Leigh Tag new-gene-name tag was added to gene: YARS.
Intellectual disability v3.144 YARS Sarah Leigh Classified gene: YARS as Amber List (moderate evidence)
Intellectual disability v3.144 YARS Sarah Leigh Added comment: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.
Intellectual disability v3.144 YARS Sarah Leigh Gene: yars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.143 YARS Sarah Leigh Tag for-review was removed from gene: YARS.
Intellectual disability v3.143 YARS Sarah Leigh commented on gene: YARS
Intellectual disability v3.143 YARS Sarah Leigh Tag new-gene-name tag was added to gene: YARS.
Intellectual disability v3.143 YARS Sarah Leigh Tag for-review tag was added to gene: YARS.
Intellectual disability v3.143 CACNB4 Sarah Leigh Deleted their comment
Intellectual disability v3.143 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Intellectual disability v3.143 CACNB4 Sarah Leigh Added comment: Comment on list classification: PMID 32176688 reports intellectual disability in homozygous sibs.
Intellectual disability v3.143 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.142 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Intellectual disability v3.142 CACNB4 Sarah Leigh Added comment: Comment on list classification: PMID 32176688 reports intellectual disability in homozygous sibs.
Intellectual disability v3.142 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh edited their review of gene: CACNB4: Added comment: There is enough evidence for this gene to be rated GREEN for epilepsy at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh Tag for-review tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to 20561025; 20378313; 10762541; 32176688 25529582
Early onset or syndromic epilepsy v2.106 CACNB4 Sarah Leigh Phenotypes for gene: CACNB4 were changed from to {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability
Early onset or syndromic epilepsy v2.105 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to
Early onset or syndromic epilepsy v2.104 CACNB4 Sarah Leigh Mode of inheritance for gene: CACNB4 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional data.
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.141 CACNB4 Sarah Leigh Mode of inheritance for gene: CACNB4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.140 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to 0
Intellectual disability v3.139 RSRC1 Sarah Leigh commented on gene: RSRC1: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.139 RSRC1 Sarah Leigh Classified gene: RSRC1 as Amber List (moderate evidence)
Intellectual disability v3.139 RSRC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in unrelated families.
Intellectual disability v3.139 RSRC1 Sarah Leigh Gene: rsrc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.138 RSRC1 Sarah Leigh Tag for-review tag was added to gene: RSRC1.
Intellectual disability v3.138 RSRC1 Sarah Leigh Publications for gene: RSRC1 were set to 28640246; 29522154; 32227164
Intellectual disability v3.137 RSRC1 Sarah Leigh Phenotypes for gene: RSRC1 were changed from Intellectual developmental disorder, autosomal recessive 70 618402 to Intellectual developmental disorder, autosomal recessive 70 618402
Intellectual disability v3.137 RSRC1 Sarah Leigh Publications for gene: RSRC1 were set to 28640246; 29522154; 32227164
Intellectual disability v3.136 RSRC1 Sarah Leigh Phenotypes for gene: RSRC1 were changed from Intellectual developmental disorder, autosomal recessive 70, MIM# 618402 to Intellectual developmental disorder, autosomal recessive 70 618402
Intellectual disability v3.136 RSRC1 Sarah Leigh Publications for gene: RSRC1 were set to 28640246; 29522154
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Zornitza Stark Deleted their comment
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Zornitza Stark edited their review of gene: OFD1: Added comment: The conditions associated with this gene are not primary ciliary dyskinesias. However, note 7 individuals reported with PCD phenotype.; Changed rating: GREEN; Changed publications: 32276433, 31373179; Changed phenotypes: Primary ciliary dyskinesia
Familial pulmonary fibrosis v1.9 SFTPA1 Zornitza Stark reviewed gene: SFTPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31601679, 30854216, 28869238, 26792177; Phenotypes: Idiopathic pulmonary fibrosis; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP74 Zornitza Stark gene: CFAP74 was added
gene: CFAP74 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: CFAP74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP74 were set to 32555313
Phenotypes for gene: CFAP74 were set to Primary ciliary dyskinesia; infertility
Review for gene: CFAP74 was set to AMBER
Added comment: Two unrelated individuals with compound het missense variants reported.
Sources: Literature
Congenital myopathy v2.5 HACD1 Zornitza Stark reviewed gene: HACD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15829503, 23933735, 32426512; Phenotypes: Congenital myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v1.3 ASPRV1 Zornitza Stark gene: ASPRV1 was added
gene: ASPRV1 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: ASPRV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASPRV1 were set to 32516568
Phenotypes for gene: ASPRV1 were set to palmoplantar keratoderma; lamellar ichthyosis
Review for gene: ASPRV1 was set to GREEN
gene: ASPRV1 was marked as current diagnostic
Added comment: -3 heterozygous missense variants identified across 4 unrelated kindreds
-mutant ASPRV1 expressed in human keratinocytes suggests impaired filaggrin processing
Sources: Literature
Ichthyosis and erythrokeratoderma v1.3 SREBF1 Zornitza Stark gene: SREBF1 was added
gene: SREBF1 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SREBF1 were set to 32497488
Phenotypes for gene: SREBF1 were set to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome
Review for gene: SREBF1 was set to GREEN
Added comment: 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. 3 different msisense variants identified affecting the same region (residues 527, 528, and 530). Functional studies support impaired function (impaired nuclear translocation of the transcriptionally active form of SREBP1 resulting in lower expression of the SREBP1 variants). Increased keratinocyte apoptosis was observed in patient scalp samples.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.14 LAMB1 Zornitza Stark reviewed gene: LAMB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29888467, 25925986; Phenotypes: Cystic leukoencephalopathy; Mode of inheritance: None
Adult onset leukodystrophy v1.4 LAMB1 Zornitza Stark gene: LAMB1 was added
gene: LAMB1 was added to White matter disorders - adult onset. Sources: Literature
Mode of inheritance for gene: LAMB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMB1 were set to 32548278
Phenotypes for gene: LAMB1 were set to Retinal Vascular Abnormality; mild intellectual disability; white matter lesions; lower limb spasticity
Review for gene: LAMB1 was set to RED
Added comment: Single adult female patient with onset of symptoms after 22yrs of age reported with novel homozygous missense variant (parents distantly related family), no further evidence of pathogenicity, however note two reports of cystic leukodystrophy in paediatric patients.
Sources: Literature
Intellectual disability v3.135 SLC12A2 Zornitza Stark gene: SLC12A2 was added
gene: SLC12A2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC12A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A2 were set to 30740830
Phenotypes for gene: SLC12A2 were set to Kilquist syndrome; deafness; intellectual disability; dysmorphic features; absent salivation; ectodermal dysplasia; constipation; intestinal malrotation; multiple congenital anomalies
Review for gene: SLC12A2 was set to GREEN
gene: SLC12A2 was marked as current diagnostic
Added comment: Two families reported and a mouse model. New report is not on PubMed yet: (https://doi.org/10.1212/NXG.0000000000000478)
Sources: Literature
Rare multisystem ciliopathy disorders v1.125 CCDC32 Zornitza Stark gene: CCDC32 was added
gene: CCDC32 was added to Rare multisystem ciliopathy disorders. Sources: Literature
Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC32 were set to 32307552
Phenotypes for gene: CCDC32 were set to Craniofacial, cardiac, laterality and neurodevelopmental anomalies
Review for gene: CCDC32 was set to GREEN
gene: CCDC32 was marked as current diagnostic
Added comment: Two unrelated consanguineous families with probands with homozygous frameshift variants reported. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and shows a role for ccdc32 in craniofacial, brain and left/right axis development.
Sources: Literature
Intellectual disability v3.135 RAP1GDS1 Zornitza Stark gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to 32431071
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability; dysmorphic features
Review for gene: RAP1GDS1 was set to AMBER
Added comment: Four individuals from two consanguineous families, same homozygous splice site variant detected, borderline Red/Amber.
Sources: Literature
Childhood solid tumours cancer susceptibility v1.6 GPR161 Zornitza Stark gene: GPR161 was added
gene: GPR161 was added to Childhood solid tumours cancer susceptibility. Sources: Literature
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPR161 were set to 31609649
Phenotypes for gene: GPR161 were set to Predisposition to paediatric medulloblastoma
Review for gene: GPR161 was set to GREEN
gene: GPR161 was marked as current diagnostic
Added comment: 6 unrelated individuals reported with germline variants, 5 with truncating, one missense and paediatric medulloblastoma. Somatic second hit in tumour tissue.
Sources: Literature
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 SUZ12 Zornitza Stark gene: SUZ12 was added
gene: SUZ12 was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Expert list
Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SUZ12 were set to 31736240; 28229514
Phenotypes for gene: SUZ12 were set to Imagawa-Matsumoto syndrome, MIM# 618786
Review for gene: SUZ12 was set to GREEN
gene: SUZ12 was marked as current diagnostic
Added comment: More than 10 unrelated individuals reported, overgrowth is a key feature of this syndrome.
Sources: Expert list
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 SETD2 Zornitza Stark gene: SETD2 was added
gene: SETD2 was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Expert list
Mode of inheritance for gene: SETD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD2 were set to 29681085
Phenotypes for gene: SETD2 were set to Luscan-Lumish syndrome, MIM#616831
Review for gene: SETD2 was set to GREEN
gene: SETD2 was marked as current diagnostic
Added comment: Multiple affected individuals with macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures
Sources: Expert list
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 RNF125 Zornitza Stark gene: RNF125 was added
gene: RNF125 was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Expert list
Mode of inheritance for gene: RNF125 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF125 were set to 25196541
Phenotypes for gene: RNF125 were set to Tenorio syndrome, MIM# 616260
Review for gene: RNF125 was set to GREEN
Added comment: At least 3 unrelated families reported, overgrowth is a key feature.
Sources: Expert list
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 PIK3CA Zornitza Stark reviewed gene: PIK3CA: Rating: GREEN; Mode of pathogenicity: None; Publications: 23246288; Phenotypes: Cowden syndrome 5, MIM# 615108; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 PDGFRB Zornitza Stark gene: PDGFRB was added
gene: PDGFRB was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Expert list
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFRB were set to 25454926; 32291752; 30941910; 29226947
Phenotypes for gene: PDGFRB were set to Kosaki overgrowth syndrome, MIM# 616592
Review for gene: PDGFRB was set to GREEN
gene: PDGFRB was marked as current diagnostic
Added comment: Multiple affected individuals reported.
Sources: Expert list
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 NFIB Zornitza Stark reviewed gene: NFIB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 DIS3L2 Zornitza Stark gene: DIS3L2 was added
gene: DIS3L2 was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Expert list
Mode of inheritance for gene: DIS3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DIS3L2 were set to 22306653; 28328139; 29950491
Phenotypes for gene: DIS3L2 were set to Perlman syndrome, MIM# 267000
Review for gene: DIS3L2 was set to GREEN
gene: DIS3L2 was marked as current diagnostic
Added comment: Neonatal macrosomia and organomegaly. At least 6 families reported (?two Dutch families founder effect), note three had CNVs. Mouse model.
Sources: Expert list
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 ASXL2 Zornitza Stark reviewed gene: ASXL2: Rating: RED; Mode of pathogenicity: None; Publications: 28061364; Phenotypes: Shashi-Pena syndrome, MIM# 617190; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.94 ABCC9 Zornitza Stark gene: ABCC9 was added
gene: ABCC9 was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Expert list
Mode of inheritance for gene: ABCC9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABCC9 were set to 22610116; 22608503
Phenotypes for gene: ABCC9 were set to Hypertrichotic osteochondrodysplasia, MIM# 239850; Cantu syndrome
Review for gene: ABCC9 was set to GREEN
Added comment: Neonatal macrosomia is a key feature of this syndrome.
Sources: Expert list
Primary lymphoedema v2.4 CHD7 Ivone Leong Tag for-review tag was added to gene: CHD7.
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Simon Thomas changed review comment from: Publication from 2019: Truncating Mutations in Exons 20 and 21 of OFD1 Can Cause Primary Ciliary Dyskinesia Without Associated Syndromic Symptoms. PMID: 31366608 DOI: 10.1136/jmedgenet-2018-105918 .
A novel hemizygous truncating mutaion in exon 20 was found by GOSH in a Wessex patient negative for our in-house PCD panel.
Sequencing of these exons could be included in the PCD panel or at least reviewed as part of amber gene data collection.; to: Publication from 2019: Truncating Mutations in Exons 20 and 21 of OFD1 Can Cause Primary Ciliary Dyskinesia Without Associated Syndromic Symptoms. PMID: 31366608 DOI: 10.1136/jmedgenet-2018-105918 .
A novel hemizygous truncating mutation in OFD1 exon 20 was found by GOSH in a Wessex patient negative for our in-house PCD panel.
Sequencing of these exons could be included in the PCD panel or at least reviewed as part of amber gene data collection.
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Simon Thomas changed review comment from: Publication from 2019: Truncating Mutations in Exons 20 and 21 of OFD1 Can Cause Primary Ciliary Dyskinesia Without Associated Syndromic Symptoms. PMID: 31366608 DOI: 10.1136/jmedgenet-2018-105918 .
A novel hemizygous truncating mutaion in exon 20 was found by GOSH in a Wessex patient negative for our in-house PCD panel.
Sequencing of these exons could be included in the PCD panels or at least reviewed as part of amber gene data collection.; to: Publication from 2019: Truncating Mutations in Exons 20 and 21 of OFD1 Can Cause Primary Ciliary Dyskinesia Without Associated Syndromic Symptoms. PMID: 31366608 DOI: 10.1136/jmedgenet-2018-105918 .
A novel hemizygous truncating mutaion in exon 20 was found by GOSH in a Wessex patient negative for our in-house PCD panel.
Sequencing of these exons could be included in the PCD panel or at least reviewed as part of amber gene data collection.
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Simon Thomas commented on gene: OFD1
Short QT syndrome v2.3 CACNA1C Zornitza Stark reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
RASopathies v1.55 MRAS Zornitza Stark changed review comment from: Two unrelated individuals reported with de novo variants in this gene. Rated as LIMITED by ClinGen.
Sources: Expert list; to: Two unrelated individuals reported with de novo variants in this gene initially. Rated as LIMITED by ClinGen in 2018. Note 4 further individuals reported since.
Sources: Expert list
RASopathies v1.55 MRAS Zornitza Stark edited their review of gene: MRAS: Changed rating: GREEN; Changed publications: 28289718, 31173466, 31108500, 31173466
RASopathies v1.55 MRAS Zornitza Stark gene: MRAS was added
gene: MRAS was added to RASopathies. Sources: Expert list
Mode of inheritance for gene: MRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAS were set to 28289718
Phenotypes for gene: MRAS were set to Noonan syndrome
Review for gene: MRAS was set to AMBER
Added comment: Two unrelated individuals reported with de novo variants in this gene. Rated as LIMITED by ClinGen.
Sources: Expert list
RASopathies v1.55 RASA2 Zornitza Stark reviewed gene: RASA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 25049390; Phenotypes: Noonan syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
RASopathies v1.55 A2ML1 Zornitza Stark reviewed gene: A2ML1: Rating: RED; Mode of pathogenicity: None; Publications: 24939586, 25862627; Phenotypes: Noonan syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
RASopathies v1.55 RRAS2 Zornitza Stark gene: RRAS2 was added
gene: RRAS2 was added to RASopathies. Sources: Expert list
Mode of inheritance for gene: RRAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAS2 were set to 31130282
Phenotypes for gene: RRAS2 were set to Noonan syndrome 12, OMIM #618624
Review for gene: RRAS2 was set to GREEN
gene: RRAS2 was marked as current diagnostic
Added comment: Six unrelated families reported
Sources: Expert list
RASopathies v1.55 RRAS Zornitza Stark gene: RRAS was added
gene: RRAS was added to RASopathies. Sources: Expert list
Mode of inheritance for gene: RRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAS were set to 24705357
Phenotypes for gene: RRAS were set to Noonan syndrome
Review for gene: RRAS was set to AMBER
Added comment: Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 ZNF462 Zornitza Stark gene: ZNF462 was added
gene: ZNF462 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF462 were set to 28513610
Phenotypes for gene: ZNF462 were set to Weiss-Kruszka syndrome, MIM# 618619
Review for gene: ZNF462 was set to GREEN
gene: ZNF462 was marked as current diagnostic
Added comment: Craniosynostosis observed in 38% of affected individuals.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SMAD3 Zornitza Stark gene: SMAD3 was added
gene: SMAD3 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: SMAD3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD3 were set to 20301312; 29392890
Phenotypes for gene: SMAD3 were set to Loeys-Dietz syndrome 3, MIM# 613795
Review for gene: SMAD3 was set to GREEN
Added comment: Craniosynostosis is a feature of LDS.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 MASP1 Zornitza Stark reviewed gene: MASP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7677137, 21258343; Phenotypes: 3MC syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 HNRNPK Zornitza Stark gene: HNRNPK was added
gene: HNRNPK was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: HNRNPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPK were set to 26173930; 26954065; 29904177
Phenotypes for gene: HNRNPK were set to Au-Kline syndrome, MIM# 616580
Review for gene: HNRNPK was set to GREEN
gene: HNRNPK was marked as current diagnostic
Added comment: Multiple unrelated individuals with Au-Kline syndrome (approx 1/3) have craniosynostosis - sagittal, metopic, lambdoid.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 FGF10 Zornitza Stark gene: FGF10 was added
gene: FGF10 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: FGF10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF10 were set to 29215649
Phenotypes for gene: FGF10 were set to Craniosynostosis
Review for gene: FGF10 was set to AMBER
Added comment: Two individuals reported with variants in this gene as part of a large craniosynostosis cohort.
Sources: Expert list
Bilateral congenital or childhood onset cataracts v2.6 RIC1 Sarah Leigh Added comment: Comment on phenotypes: Pediatric posterior lenticonus cataract and global developmental delay
Bilateral congenital or childhood onset cataracts v2.6 RIC1 Sarah Leigh Phenotypes for gene: RIC1 were changed from Pediatric posterior lenticonus cataract and global developmental delay to CATIFA syndrome 618761
Bilateral congenital or childhood onset cataracts v2.5 RIC1 Sarah Leigh Publications for gene: RIC1 were set to 27878435
Bilateral congenital or childhood onset cataracts v2.4 RIC1 Sarah Leigh Classified gene: RIC1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.4 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Bilateral congenital or childhood onset cataracts v2.4 RIC1 Sarah Leigh Gene: ric1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.3 RIC1 Sarah Leigh Tag watchlist tag was added to gene: RIC1.
Intellectual disability v3.135 RIC1 Sarah Leigh Deleted their comment
Intellectual disability v3.135 RIC1 Sarah Leigh Publications for gene: RIC1 were set to 31932796
Intellectual disability v3.134 RIC1 Sarah Leigh Classified gene: RIC1 as Amber List (moderate evidence)
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.134 RIC1 Sarah Leigh Gene: ric1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.134 RIC1 Sarah Leigh Classified gene: RIC1 as Amber List (moderate evidence)
Intellectual disability v3.134 RIC1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least one variant reported in numerous members of two families, who shared an autozygous interval, confirming Founder effect (PMID 27878435). Segregation was demonstrated, together with supportive functional and zebra fish model (PMID 31932796).
Intellectual disability v3.134 RIC1 Sarah Leigh Gene: ric1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.133 RIC1 Sarah Leigh Tag watchlist tag was added to gene: RIC1.
Intellectual disability v3.133 RIC1 Sarah Leigh Phenotypes for gene: RIC1 were changed from Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to CATIFA syndrome 618761; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Intellectual disability v3.132 OTUD7A Sarah Leigh Classified gene: OTUD7A as Red List (low evidence)
Intellectual disability v3.132 OTUD7A Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Intellectual disability v3.132 OTUD7A Sarah Leigh Gene: otud7a has been classified as Red List (Low Evidence).
Intellectual disability v3.131 ISCA-46295-Loss Sarah Leigh Publications for Region: ISCA-46295-Loss were set to 19898479; 20236110; 22775350
Intellectual disability v3.130 TOMM70 Eleanor Williams changed review comment from: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature; to: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. Patient 1 showed severe global developmental delay. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.130 TOMM70 Eleanor Williams gene: TOMM70 was added
gene: TOMM70 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TOMM70 were set to 31907385; 32356556
Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis; developmental delay; white matter abnormalities
Review for gene: TOMM70 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM or Gene2Phenotype

PMID: 31907385 - Wei et al 2020 - report a patient with severe anemia, lactic acidosis, and developmental delay in which two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] were identified. Functional studies showed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects. Abstract only accessed.

PMID: 32356556 - Dutta et al 2020 - report 2 patients with de novo heterozygous missense variants in the C-terminal region of TOMM70. Both patients had shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities. However, for patient 1 a neurodevelopmental disorder was noted in infancy, but patient 2 developed as normal until age 4 when neurological regression occurred. Some functional data from Drosophila show that the variants cause partial loss of function.

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.129 CAPZA2 Eleanor Williams Phenotypes for gene: CAPZA2 were changed from to intellectual disability
Intellectual disability v3.128 CAPZA2 Eleanor Williams Classified gene: CAPZA2 as Amber List (moderate evidence)
Intellectual disability v3.128 CAPZA2 Eleanor Williams Added comment: Comment on list classification: 2 cases reported. Some functional evidence but not enough to promote to green.
Intellectual disability v3.128 CAPZA2 Eleanor Williams Gene: capza2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.127 CAPZA2 Eleanor Williams gene: CAPZA2 was added
gene: CAPZA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPZA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPZA2 were set to 32338762
Review for gene: CAPZA2 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM.

PMID: 32338762 - Huang et al 2020 - report 2 unrelated families (Chinese and European) in which a de novo heterozygous variant has been identified in CAPZA2 in paediatric probands that present with global motor development delay, speech delay, intellectual disability, hypotonia. One proband had seizures at 7 months but these were controlled with medication and did not repeat. The other proband at age one had an atypical febrile seizure that was controlled without medication. Functional studies in Drosophila suggest that these variants are mild loss of function mutations but that they can act as dominant negative variants in actin polymerization in bristles.
Sources: Literature
Radial dysplasia v1.10 RAD21 Sarah Leigh Classified gene: RAD21 as Green List (high evidence)
Radial dysplasia v1.10 RAD21 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for CRANIOECTODERMAL DYSPLASIA. At least 4 variants reported.
Radial dysplasia v1.10 RAD21 Sarah Leigh Gene: rad21 has been classified as Green List (High Evidence).
Radial dysplasia v1.9 RAD21 Sarah Leigh Publications for gene: RAD21 were set to 22633399; 31334757]
Radial dysplasia v1.8 RAD21 Sarah Leigh Publications for gene: RAD21 were set to 22633399
Monogenic hearing loss v2.37 CNRIP1 Eleanor Williams changed review comment from: PMID: 32337552 - ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature; to: PMID: 32337552 - Lezirovitz et al 2020 ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Monogenic hearing loss v2.37 PPP3R1 Eleanor Williams gene: PPP3R1 was added
gene: PPP3R1 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: PPP3R1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP3R1 were set to 32337552; 19159392
Phenotypes for gene: PPP3R1 were set to Deafness, autosomal dominant 58 MIM#615654
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Monogenic hearing loss v2.36 PLEK Eleanor Williams gene: PLEK was added
gene: PLEK was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: PLEK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEK were set to 32337552; 19159392
Phenotypes for gene: PLEK were set to Deafness, autosomal dominant 58 MIM#615654
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Monogenic hearing loss v2.35 CNRIP1 Eleanor Williams gene: CNRIP1 was added
gene: CNRIP1 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: CNRIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNRIP1 were set to 32337552; 19159392
Phenotypes for gene: CNRIP1 were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: CNRIP1 was set to RED
Added comment: PMID: 32337552 - ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 B3GAT3 Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31438591; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 ACTG2 Zornitza Stark gene: ACTG2 was added
gene: ACTG2 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: ACTG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ACTG2 were set to Baraitser-Winter syndrome 2, MIM# 614583
Review for gene: ACTG2 was set to GREEN
Added comment: Metopic ridging is a key feature of this condition.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 ACTB Zornitza Stark gene: ACTB was added
gene: ACTB was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: ACTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ACTB were set to Baraitser-Winter syndrome 1, MIM# 243310
Review for gene: ACTB was set to GREEN
Added comment: Ridged metopic suture is a key feature of this condition.
Sources: Expert list
Vascular skin disorders v1.3 STAMBP Zornitza Stark gene: STAMBP was added
gene: STAMBP was added to Vascular skin disorders. Sources: Expert list
Mode of inheritance for gene: STAMBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAMBP were set to 23542699
Phenotypes for gene: STAMBP were set to Microcephaly-capillary malformation syndrome, MIM# 614261
Review for gene: STAMBP was set to GREEN
Added comment: Nine families reported in the original publication.
Sources: Expert list
Vascular skin disorders v1.3 PIK3R2 Zornitza Stark reviewed gene: PIK3R2: Rating: RED; Mode of pathogenicity: None; Publications: 22729224, 28502725; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, MIM# 603387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Vascular skin disorders v1.3 FOXC2 Zornitza Stark reviewed gene: FOXC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphedema-distichiasis syndrome, MIM# 153400; Mode of inheritance: None
Vascular skin disorders v1.3 FLT4 Zornitza Stark reviewed gene: FLT4: Rating: RED; Mode of pathogenicity: None; Publications: 11807987; Phenotypes: Hemangioma, capillary infantile, somatic, MIM# 602089; Mode of inheritance: None
Vascular skin disorders v1.3 F12 Zornitza Stark reviewed gene: F12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Vascular skin disorders v1.3 CCBE1 Zornitza Stark reviewed gene: CCBE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hennekam lymphangiectasia-lymphedema syndrome 1 235510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Vascular skin disorders v1.3 ALAS2 Zornitza Stark reviewed gene: ALAS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Vascular skin disorders v1.3 AKT3 Zornitza Stark gene: AKT3 was added
gene: AKT3 was added to Vascular skin disorders. Sources: Expert list
Mode of inheritance for gene: AKT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AKT3 were set to 23745724; 22729224
Phenotypes for gene: AKT3 were set to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (615937)
Mode of pathogenicity for gene: AKT3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: AKT3 was set to GREEN
gene: AKT3 was marked as current diagnostic
Added comment: Established cause of Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (615937). Capillary malformations reported in PMID 23745724 & 22729224, both cases de novo AKT3 variants.
Sources: Expert list
Vascular skin disorders v1.3 ADAMTS13 Zornitza Stark reviewed gene: ADAMTS13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombotic thrombocytopenic purpura, hereditary 274150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.34 ABCC1 Eleanor Williams Classified gene: ABCC1 as Amber List (moderate evidence)
Monogenic hearing loss v2.34 ABCC1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber based on expert review and some cases reported.
Monogenic hearing loss v2.34 ABCC1 Eleanor Williams Gene: abcc1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.33 ABCC1 Eleanor Williams Phenotypes for gene: ABCC1 were changed from Nonsyndromic hearing loss to Nonsyndromic hearing loss; ?Deafness, autosomal dominant 77, 618915
Monogenic hearing loss v2.32 ABCC1 Eleanor Williams commented on gene: ABCC1
Monogenic hearing loss v2.32 HOMER2 Eleanor Williams Classified gene: HOMER2 as Amber List (moderate evidence)
Monogenic hearing loss v2.32 HOMER2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. Two families with monoallelic variants, and a mouse with biallelic variants and deafness. Heterozygous mice did not show hearing loss so promoting to amber not green just now. Genomics England clinical team support this rating.
Monogenic hearing loss v2.32 HOMER2 Eleanor Williams Gene: homer2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.31 ELMOD3 Eleanor Williams Phenotypes for gene: ELMOD3 were changed from ?Deafness, autosomal recessive 88, 615429 to ?Deafness, autosomal recessive 88, 615429; Deafness, autosomal dominant
Monogenic hearing loss v2.30 ELMOD3 Eleanor Williams Publications for gene: ELMOD3 were set to
Monogenic hearing loss v2.29 ELMOD3 Eleanor Williams Mode of inheritance for gene: ELMOD3 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.28 ELMOD3 Eleanor Williams Classified gene: ELMOD3 as Amber List (moderate evidence)
Monogenic hearing loss v2.28 ELMOD3 Eleanor Williams Added comment: Comment on list classification: Although there are 2 SNV cases plus a mouse model the mode of inheritance differs. In another case there is a multigene deletion. Promoting from red to amber for now, and will wait for further cases to determine clarity on the mode of inheritance. Amber rating supported by the Genomics England clinical team.
Monogenic hearing loss v2.28 ELMOD3 Eleanor Williams Gene: elmod3 has been classified as Amber List (Moderate Evidence).
CAKUT v1.153 CHD1L Eleanor Williams Classified gene: CHD1L as Red List (low evidence)
CAKUT v1.153 CHD1L Eleanor Williams Added comment: Comment on list classification: Following expert review that some of the reported variants in this gene are relatively common in gnomAD and therefore unlikely to associated with a Mendelian disease, downgrading this gene from amber to red.
CAKUT v1.153 CHD1L Eleanor Williams Gene: chd1l has been classified as Red List (Low Evidence).
Renal ciliopathies v1.23 BBIP1 Eleanor Williams Publications for gene: BBIP1 were set to 24026985
Renal ciliopathies v1.22 BBIP1 Eleanor Williams Classified gene: BBIP1 as Amber List (moderate evidence)
Renal ciliopathies v1.22 BBIP1 Eleanor Williams Added comment: Comment on list classification: Updating this gene from red to amber as an additional case has now been reported, bringing the total to 2.
Renal ciliopathies v1.22 BBIP1 Eleanor Williams Gene: bbip1 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.21 DCDC2 Eleanor Williams Classified gene: DCDC2 as Amber List (moderate evidence)
Renal ciliopathies v1.21 DCDC2 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber as there are now two cases where Nephronophthisis has been reported in patients with biallelic variants in this gene.
Renal ciliopathies v1.21 DCDC2 Eleanor Williams Gene: dcdc2 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.20 DCDC2 Eleanor Williams Publications for gene: DCDC2 were set to 25557784 - in vitro/in vivo evidence; 22558177 - expression data for the transcriptome of ciliated cells; 27319779 - biallelic missense variants reported in four affected children with Neonatal sclerosing cholangitis; 27469900 - 7 out of 24 patients with 7 with biallelic protein-truncating variants in DCDC2 (6 of 19 families)
Renal ciliopathies v1.19 DCDC2 Eleanor Williams commented on gene: DCDC2: Comments taken from the publications field before tidying up

25557784 - in vitro/in vivo evidence
22558177 - expression data for the transcriptome of ciliated cells
27319779 - biallelic missense variants reported in four affected children with Neonatal sclerosing cholangitis
27469900 - 7 out of 24 patients with 7 with biallelic protein-truncating variants in DCDC2 (6 of 19 families)
Renal ciliopathies v1.19 DCDC2 Eleanor Williams changed review comment from: As Zornitza Stark has noted PMID: 31821705 - Slater et al 2020 provides a second case where nephronophthisis is noted.; to: As Zornitza Stark has noted PMID: 31821705 - Slater et al 2020 provides a second case where nephronophthisis is noted in a patient with a homozygous c.383C>G (p.S128*) nonsense pathogenic variant in exon 3 of the DCDC2 gene. Exome sequencing also showed variants of unknown clinical significance (VUS) in five other disease genes possibly related to the clinical phenotype. Parental samples were not available.
Renal ciliopathies v1.19 DCDC2 Eleanor Williams reviewed gene: DCDC2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.126 HARS Zornitza Stark changed review comment from: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature; to: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition. We have also added to paediatric ataxia panel as Amber.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature
Intellectual disability v3.126 HARS Zornitza Stark gene: HARS was added
gene: HARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS were set to 32296180
Phenotypes for gene: HARS were set to multisystem ataxic syndrome; mild-severe intellectual disability
Review for gene: HARS was set to AMBER
Added comment: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition.

Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT.
Sources: Literature
Fetal anomalies v1.73 ACVR2B Zornitza Stark reviewed gene: ACVR2B: Rating: RED; Mode of pathogenicity: None; Publications: 9916847, 30622330, 21864452; Phenotypes: Heterotaxy, visceral, 4, autosomal 613751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v1.5 EMILIN1 Zornitza Stark gene: EMILIN1 was added
gene: EMILIN1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: EMILIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMILIN1 were set to 31978608; 26462740
Phenotypes for gene: EMILIN1 were set to Peripheral neuropathy; aortic aneurysm
Review for gene: EMILIN1 was set to AMBER
Added comment: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 SELENON Zornitza Stark reviewed gene: SELENON: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.126 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration. We have added to the Microcephaly and Genetic Epilepsies panels as well.
Sources: Literature
Intellectual disability v3.126 HNRNPH1 Zornitza Stark gene: HNRNPH1 was added
gene: HNRNPH1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPH1 were set to 32335897; 29938792
Phenotypes for gene: HNRNPH1 were set to HNRNPH1‐related syndromic intellectual disability
Review for gene: HNRNPH1 was set to GREEN
Added comment: 1st patient reported in 2018 with intellectual disability and dysmorphic features and HNRNPH1 heterozygous missense variant. 2020 paper reports additional 7 cases with ID, short stature, microcephaly, distinctive dysmorphic facial features, and congenital anomalies (cranial, brain, genitourinary, palate, ophthalmologic). They all had HNRNPH1 heterozygous pathogenic variants (missense, frameshift, in‐frame deletion, entire gene duplication) and were identified using clinical networks and GeneMatcher.
Sources: Literature
Intellectual disability v3.126 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to microcephaly; Intellectual disability
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.7 NME5 Zornitza Stark gene: NME5 was added
gene: NME5 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: NME5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NME5 were set to 32185794
Phenotypes for gene: NME5 were set to Primary ciliary dyskinesia
Review for gene: NME5 was set to AMBER
Added comment: One patient reported with PCD with situs solitus, with radial spokes (RS) and central pair (CP) defects. Patient had a homozygous nonsense variant in NME5, with parents as carriers. Morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy.
Sources: Literature
Familial non syndromic congenital heart disease v1.51 ADAMTS19 Zornitza Stark changed review comment from: 2020 paper reports 3 additional consanguineous families (2 affected sibs in each) with anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. All 3 families had homozygous LoF variants in ADAMTS19, which segregated with disease. No functional studies. Previously reported 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype; to: New 2020 paper reports 3 additional consanguineous families (2 affected sibs in each) with anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. All 3 families had homozygous LoF variants in ADAMTS19, which segregated with disease. No functional studies. Previously reported 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Familial non syndromic congenital heart disease v1.51 ADAMTS19 Zornitza Stark edited their review of gene: ADAMTS19: Added comment: 2020 paper reports 3 additional consanguineous families (2 affected sibs in each) with anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. All 3 families had homozygous LoF variants in ADAMTS19, which segregated with disease. No functional studies. Previously reported 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype; Changed rating: GREEN; Changed publications: 31844321, 32323311
Fetal anomalies v1.73 TMEM94 Rhiannon Mellis gene: TMEM94 was added
gene: TMEM94 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM94 were set to PMID: 30526868
Phenotypes for gene: TMEM94 were set to Intellectual developmental disorder with cardiac defects and dysmorphic facies
Review for gene: TMEM94 was set to GREEN
Added comment: Literature reports 10 patients from 6 unrelated families, and a mouse model PMID: 30526868

Reviewed with Prof Lyn Chitty for fetally relevant phenotype (Yes - Congenital heart malformations including: Atrial septal defect; Ventricular septal defect; Pulmonary hypoplasia; Pulmonary atresia; Tetralogy of Fallot; Double outlet right ventricle
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v2.102 MCM3AP Eleanor Williams gene: MCM3AP was added
gene: MCM3AP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM3AP were set to 32202298
Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 618124
Review for gene: MCM3AP was set to RED
Added comment: PMID: 32202298 - Woldegebriel et al 2020 - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.
Sources: Literature
Fetal anomalies v1.73 GDF1 Rhiannon Mellis gene: GDF1 was added
gene: GDF1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: GDF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GDF1 were set to PMID: 20413652; 28991257; 17924340
Phenotypes for gene: GDF1 were set to Congenital heart defects, multiple types; Right atrial isomerism (Ivemark)
Review for gene: GDF1 was set to GREEN
Added comment: Right atrial isomerism (AR): 5 sibs in one family PMID: 20413652; One unrelated individual with RAI, complex cardiac anomalies, abdominal heterotaxy and asplenia PMID: 28991257

Other varied CHD (including ToF, DORV, TGA) (AD): 8 unrelated individuals PMID 17924340

Reviewed for fetally relevant phenotype by Prof Lyn Chitty (Yes)

This gene appears on our local heterotaxy panel (NETRGL) and as Green on Panelapp Laterality disorders panel and Familial non-syndromic CHD panel.
Sources: Literature, Expert Review
Fetal anomalies v1.73 CFAP53 Rhiannon Mellis gene: CFAP53 was added
gene: CFAP53 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: CFAP53 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP53 were set to PMID: 22577226; PMID: 25504577; PMID: 26531781
Phenotypes for gene: CFAP53 were set to Heterotaxy, visceral, 6, autosomal recessive; Dextrocardia; Transposition of the great arteries; gut malrotation; midline liver; inverted spleen
Review for gene: CFAP53 was set to GREEN
Added comment: Literature reports 6 individuals from 4 families and a zebrafish model PMID: 22577226, PMID: 25504577, PMID: 26531781

Reviewed for fetally relevant phenotype by Prof Lyn Chitty (yes).

This gene appears on our local heterotaxy panel (NETRGL) and on the Panelapp laterality disorders and non-syndromic CHD panels (Green)
Sources: Literature, Expert Review
Intellectual disability v3.126 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295; 32202298
Fetal anomalies v1.73 ACVR2B Rhiannon Mellis gene: ACVR2B was added
gene: ACVR2B was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: ACVR2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACVR2B were set to PMID: 9916847; PMID: 9242489
Phenotypes for gene: ACVR2B were set to Heterotaxy; Dextrocardia; Double outlet right ventricle; Transposition of the great arteries; Gut malrotation; polysplenia; right-sided spleen; asplenia
Review for gene: ACVR2B was set to GREEN
Added comment: Reported in literature 3 unrelated cases PMID: 9916847 and a mouse model PMID: 9242489

Reviewed by Prof Lyn Chitty for fetally relevant phenotype (yes).

This gene is included in our local heterotaxy panel (NETRGL).
Sources: Expert Review, Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19576565, 28803818, 31266720; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 MIM#612937; Mode of inheritance: None; Current diagnostic: yes
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 MYOT Zornitza Stark reviewed gene: MYOT: Rating: AMBER; Mode of pathogenicity: None; Publications: 30055862, 21336781, 15947064; Phenotypes: Myopathy, myofibrillar, 3 (MIM#609200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm or dissection (GMS) v1.3 FOXE3 Zornitza Stark reviewed gene: FOXE3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: Aortic aneurysm, familial thoracic 11, (susceptibility to) 617349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.125 RBL2 Sarah Leigh Deleted their comment
Intellectual disability v3.125 RBL2 Sarah Leigh Deleted their comment
Intellectual disability v3.125 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295; 32202298
Intellectual disability v3.124 COG4 Sarah Leigh reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.124 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295; 32202298
Intellectual disability v3.124 COG4 Sarah Leigh Tag for-review tag was added to gene: COG4.
Intellectual disability v3.124 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295
Intellectual disability v3.123 MCM3AP Eleanor Williams reviewed gene: MCM3AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32202298; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.123 RBL2 Sarah Leigh Classified gene: RBL2 as Red List (low evidence)
Intellectual disability v3.123 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.123 RBL2 Sarah Leigh Gene: rbl2 has been classified as Red List (Low Evidence).
Hereditary neuropathy or pain disorder v1.5 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to 28633435
Intellectual disability v3.122 SOX6 Sarah Leigh Tag for-review tag was added to gene: SOX6.
Hereditary neuropathy or pain disorder v1.4 MCM3AP Eleanor Williams reviewed gene: MCM3AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32202298; Phenotypes: peripheral neuropathy with or without impaired intellectual development, 618124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.122 SOX6 Sarah Leigh edited their review of gene: SOX6: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.122 SOX6 Sarah Leigh Classified gene: SOX6 as Amber List (moderate evidence)
Intellectual disability v3.122 SOX6 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SOX6-related neurodevelopmental syndrome. At least 17 unrelated cases, with 14 de novo heterozygous variants, a further 2 families where the variant appeared to inherited from the affected father and a single case where the variant was found to be mosaic in the unaffected father.
Intellectual disability v3.122 SOX6 Sarah Leigh Gene: sox6 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy v1.369 MCM3AP Eleanor Williams Publications for gene: MCM3AP were set to
Hereditary neuropathy v1.368 MCM3AP Eleanor Williams reviewed gene: MCM3AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32202298; Phenotypes: peripheral neuropathy with or without impaired intellectual development, 618124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.121 RBL2 Sarah Leigh Classified gene: RBL2 as Red List (low evidence)
Intellectual disability v3.121 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.121 RBL2 Sarah Leigh Gene: rbl2 has been classified as Red List (Low Evidence).
Intellectual disability v3.120 TTC5 Sarah Leigh edited their review of gene: TTC5: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.120 TTC5 Sarah Leigh Classified gene: TTC5 as Amber List (moderate evidence)
Intellectual disability v3.120 TTC5 Sarah Leigh Added comment: Comment on list classification: Not associated with a relevant phenotype in OMIM and as probable Gen2Phen gene for TTC5-associated neurodevelopmental disorder. At least 7 cases with biallelic variants.
Intellectual disability v3.120 TTC5 Sarah Leigh Gene: ttc5 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.11 TBX5 Eleanor Williams Publications for gene: TBX5 were set to 8730285
Limb disorders v2.10 TBX5 Eleanor Williams reviewed gene: TBX5: Rating: ; Mode of pathogenicity: None; Publications: 31373354; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.119 TTC5 Sarah Leigh Tag for-review tag was added to gene: TTC5.
Intellectual disability v3.119 RBL2 Sarah Leigh Classified gene: RBL2 as Red List (low evidence)
Intellectual disability v3.119 RBL2 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Identified as a candidate gene in PMIDs 32105419; 9806916, with two variants in sibblings.
Intellectual disability v3.119 RBL2 Sarah Leigh Gene: rbl2 has been classified as Red List (Low Evidence).
COVID-19 research v1.58 CTSL Arina Puzriakova reviewed gene: CTSL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Early onset or syndromic epilepsy v2.101 DMXL2 Eleanor Williams Added comment: Comment on mode of inheritance: All cases with epilepsy have been biallelic
Early onset or syndromic epilepsy v2.101 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Classified gene: DMXL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber for now. There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Gene: dmxl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.99 DMXL2 Eleanor Williams Phenotypes for gene: DMXL2 were changed from Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113 to Epileptic encephalopathy, early infantile, 81, MIM 618663; Ohtahara syndrome
Early onset or syndromic epilepsy v2.98 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.97 DMXL2 Eleanor Williams reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31688942, 30237576; Phenotypes: Ohtahara syndrome, Epileptic encephalopathy, early infantile, 81, 618663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.118 SIX5 Sarah Leigh Deleted their comment
Intellectual disability v3.118 SIX5 Sarah Leigh Classified gene: SIX5 as Red List (low evidence)
Intellectual disability v3.118 SIX5 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.118 SIX5 Sarah Leigh Gene: six5 has been classified as Red List (Low Evidence).
Intellectual disability v3.117 SKIV2L Sarah Leigh Classified gene: SKIV2L as Red List (low evidence)
Intellectual disability v3.117 SKIV2L Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.117 SKIV2L Sarah Leigh Gene: skiv2l has been classified as Red List (Low Evidence).
Intellectual disability v3.116 SKIV2L Sarah Leigh Publications for gene: SKIV2L were set to
Intellectual disability v3.115 SIX5 Sarah Leigh Publications for gene: SIX5 were set to
Intellectual disability v3.115 SIX5 Sarah Leigh Classified gene: SIX5 as Red List (low evidence)
Intellectual disability v3.115 SIX5 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.115 SIX5 Sarah Leigh Gene: six5 has been classified as Red List (Low Evidence).
Intellectual disability v3.114 SIX1 Sarah Leigh Publications for gene: SIX1 were set to 25529582; Version 12 ukgtn.nhs.uk
Intellectual disability v3.113 SIX1 Sarah Leigh Classified gene: SIX1 as Red List (low evidence)
Intellectual disability v3.113 SIX1 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability in publications.
Intellectual disability v3.113 SIX1 Sarah Leigh Gene: six1 has been classified as Red List (Low Evidence).
Intellectual disability v3.112 SIX1 Sarah Leigh Publications for gene: SIX1 were set to
Intellectual disability v3.112 SIX1 Sarah Leigh Classified gene: SIX1 as Red List (low evidence)
Intellectual disability v3.112 SIX1 Sarah Leigh Added comment: Comment on list classification: Based on expert review and lack evidence for association with intellectual disability.
Intellectual disability v3.112 SIX1 Sarah Leigh Gene: six1 has been classified as Red List (Low Evidence).
Intellectual disability v3.111 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to 21123949; 16311588; 16311588
Intellectual disability v3.110 SLC1A1 Sarah Leigh Classified gene: SLC1A1 as Amber List (moderate evidence)
Intellectual disability v3.110 SLC1A1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in 2 unrelated cases (PMID 21123949), a SLC1A1 null mouse model with age-dependent chronic neurodegeneration (PMID 16311588), together with historic reports of intellectual disability associated with the phenotype (PMID 894411).
Intellectual disability v3.110 SLC1A1 Sarah Leigh Gene: slc1a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.109 SLC1A1 Sarah Leigh reviewed gene: SLC1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.109 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from Dicarboxylic aminoaciduria 222730 to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.108 SLC1A1 Sarah Leigh Tag for-review tag was added to gene: SLC1A1.
Intellectual disability v3.108 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from Dicarboxylic aminoaciduria 222730 to Dicarboxylic aminoaciduria 222730
Intellectual disability v3.107 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to 21123949; 21123949
Intellectual disability v3.106 SLC1A1 Sarah Leigh Publications for gene: SLC1A1 were set to Dicarboxylic aminoaciduria, MIM#222730
Intellectual disability v3.105 SLC1A1 Sarah Leigh Phenotypes for gene: SLC1A1 were changed from to Dicarboxylic aminoaciduria 222730
Monogenic hearing loss v2.27 DMXL2 Eleanor Williams Tag for-review tag was added to gene: DMXL2.
Monogenic hearing loss v2.27 DMXL2 Eleanor Williams Classified gene: DMXL2 as Amber List (moderate evidence)
Monogenic hearing loss v2.27 DMXL2 Eleanor Williams Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Monogenic hearing loss v2.27 DMXL2 Eleanor Williams Gene: dmxl2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.26 DMXL2 Eleanor Williams Phenotypes for gene: DMXL2 were changed from Sensorineural Hearing Loss; ORPHA90636; OMIM:612186 to ?Deafness, autosomal dominant 71, 617605; Epileptic encephalopathy, early infantile, 81, 618663
Monogenic hearing loss v2.25 DMXL2 Eleanor Williams Publications for gene: DMXL2 were set to 27657680; 22875945; 25248098
Monogenic hearing loss v2.24 DMXL2 Eleanor Williams Added comment: Comment on mode of inheritance: updating to both monoallelic and biallelic, as deafness with both type of inheritance are reported, although more with biallelic
Monogenic hearing loss v2.24 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.23 DMXL2 Eleanor Williams edited their review of gene: DMXL2: Added comment: After consultation with Genomics England clinical team it has been decided to rate this gene green as, although hearing loss presents with epileptic encephalopathy, hearing loss is a consistent and early feature.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.104 DMD Sarah Leigh commented on gene: DMD
Monogenic hearing loss v2.23 HARS2 Eleanor Williams Tag for-review tag was added to gene: HARS2.
Monogenic hearing loss v2.23 HARS2 Eleanor Williams Classified gene: HARS2 as Amber List (moderate evidence)
Monogenic hearing loss v2.23 HARS2 Eleanor Williams Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review
Monogenic hearing loss v2.23 HARS2 Eleanor Williams Gene: hars2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.22 EPS8L2 Eleanor Williams Tag for-review tag was added to gene: EPS8L2.
Monogenic hearing loss v2.22 EPS8L2 Eleanor Williams Classified gene: EPS8L2 as Amber List (moderate evidence)
Monogenic hearing loss v2.22 EPS8L2 Eleanor Williams Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review
Monogenic hearing loss v2.22 EPS8L2 Eleanor Williams Gene: eps8l2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.21 COL4A6 Eleanor Williams Tag for-review tag was added to gene: COL4A6.
Monogenic hearing loss v2.21 CDC14A Eleanor Williams Tag for-review tag was added to gene: CDC14A.
Monogenic hearing loss v2.21 CDC14A Eleanor Williams Classified gene: CDC14A as Amber List (moderate evidence)
Monogenic hearing loss v2.21 CDC14A Eleanor Williams Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review
Monogenic hearing loss v2.21 CDC14A Eleanor Williams Gene: cdc14a has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.20 AIFM1 Eleanor Williams Tag for-review tag was added to gene: AIFM1.
Monogenic hearing loss v2.20 AIFM1 Eleanor Williams Classified gene: AIFM1 as Amber List (moderate evidence)
Monogenic hearing loss v2.20 AIFM1 Eleanor Williams Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review
Monogenic hearing loss v2.20 AIFM1 Eleanor Williams Gene: aifm1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 PNPLA2 Zornitza Stark gene: PNPLA2 was added
gene: PNPLA2 was added to Limb girdle muscular dystrophy. Sources: Expert list
Mode of inheritance for gene: PNPLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA2 were set to 32269696; 21544567
Phenotypes for gene: PNPLA2 were set to Neutral lipid storage disease with myopathy 610717
Review for gene: PNPLA2 was set to GREEN
Added comment: PMID: 32269696 - 1 patient with both upper and lower limb weakness. She had elevated CK levels, with onset >25 years old.

PMID: 21544567 - 6 patients with distal muscle weakness, shoulder girdle weakness and elevated CK levels. Severe dystrophic features of the shoulder girdle noted in 3/3 patients analysed by whole body MRI. Proximal muscle weakness was generalised first, with lower limbs affected in the 3rd/4th decade of life. Earliest age of onset 29 years old, 5/6 patients had homozygous PTCs.

Phenotypic overlap with LGMD.
Sources: Expert list
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 PFKM Zornitza Stark reviewed gene: PFKM: Rating: AMBER; Mode of pathogenicity: None; Publications: 24427140, 27066546; Phenotypes: Glycogen storage disease VII (MIM#232800); Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 CASQ1 Zornitza Stark changed review comment from: PMID: 26136523 - 3 unrelated families (10 patients) with a founder missense (p.Asp244Gly) with muscle weaknesses. All patients reported adult onset. 1 proband reported lower limb hypertrophy with normal EMG results. 6 patients had muscle biopsy, with minimal fibre size variation, and a few central nuclei. PMID: 30258016 - 12 families (22 patients), or which 21 had the recurring p.Asp244Gly mutation. Patients all had adult onset, elevated CK, with slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Pelvic girdle weakness was reported in 4/22 patients. Very large number of individuals reported with same founder variant, consider promoting to Green.; to: PMID: 26136523 - 3 unrelated families (10 patients) with a founder missense (p.Asp244Gly) with muscle weaknesses. All patients reported adult onset. 1 proband reported lower limb hypertrophy with normal EMG results. 6 patients had muscle biopsy, with minimal fibre size variation, and a few central nuclei. PMID: 30258016 - 12 families (22 patients), or which 21 had the recurring p.Asp244Gly mutation. Patients all had adult onset, elevated CK, with slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Pelvic girdle weakness was reported in 4/22 patients. Very large number of individuals reported with same founder variant, consider promoting to Green. Italian rather than rare, isolated population.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 CASQ1 Zornitza Stark reviewed gene: CASQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26136523, 30258016; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates, MIM#616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 PYROXD1 Zornitza Stark gene: PYROXD1 was added
gene: PYROXD1 was added to Limb girdle muscular dystrophy. Sources: Expert list
Mode of inheritance for gene: PYROXD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PYROXD1 were set to 30345904; 30515627; 27745833
Phenotypes for gene: PYROXD1 were set to Myopathy, myofibrillar, 8, 617258; adult-onset limb girdle muscular dystrophy
Review for gene: PYROXD1 was set to AMBER
Added comment: Reported in >3 families, but phenotype varies from early onset myopathy to a later, more LGMD-like presentation. Recurring variant, Asn155ser, identified in multiple families of different ethnicity. Age of onset variable between families. Mostly normal CK levels PMID: 30345904: 1 family reported with Asn155Ser variant. Normal CK level. Progressive muscle weakness began at the age of 9. PMID: 30515627: 3 Finnish families reported, Asn155Ser, reported on at least one allele. Patients presented with LGMD-type phenotype, onset >20. EMG showed myopathic changes. Normal CK levels. PMID: 27745833: 5 families reported (includes 2 consang Turkish families, hom Asn155Ser). Authors concluded gene as causative for early-onset myopathy, normal to moderately elevated CK levels. EMG was myopathic in all individuals tested
Sources: Expert list
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 BVES Zornitza Stark reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642364, 32528171, 31119192; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 25 616812; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 STIM1 Zornitza Stark reviewed gene: STIM1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy, tubular aggregate, 1 (MIM#160565), Stormorken syndrome (MIM#185070); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital disorders of glycosylation v2.12 PIGS Sarah Leigh Tag for-review tag was added to gene: PIGS.
Congenital disorders of glycosylation v2.12 PIGS Sarah Leigh edited their review of gene: PIGS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Congenital disorders of glycosylation v2.12 PIGS Sarah Leigh Phenotypes for gene: PIGS were changed from Glycosylphosphatidylinositol biosynthesis defect 18 618143 to Glycosylphosphatidylinositol biosynthesis defect 18 618143
Congenital disorders of glycosylation v2.11 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.11 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Congenital disorders of glycosylation v2.11 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.97 PIGS Sarah Leigh Tag watchlist tag was added to gene: PIGS.
Early onset or syndromic epilepsy v2.97 PIGS Sarah Leigh Phenotypes for gene: PIGS were changed from Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143 to Glycosylphosphatidylinositol biosynthesis defect 18 618143
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases, seizures were evident in 2 unrelated cases.
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.104 PIGS Sarah Leigh edited their review of gene: PIGS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.104 PIGS Sarah Leigh Deleted their comment
Intellectual disability v3.104 PIGS Sarah Leigh Deleted their comment
Intellectual disability v3.104 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Intellectual disability v3.104 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Intellectual disability v3.104 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.103 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Intellectual disability v3.103 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
Intellectual disability v3.103 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.103 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Intellectual disability v3.103 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases.
THIS GENE COULD BE RATED GREEN AT THE NEXT MAJOR REVIEW
Intellectual disability v3.103 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.102 PIGS Sarah Leigh Tag for-review tag was added to gene: PIGS.
Intellectual disability v3.102 PIGS Sarah Leigh Phenotypes for gene: PIGS were changed from Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143 to Glycosylphosphatidylinositol biosynthesis defect 18 618143
Renal ciliopathies v1.19 PDE6D Eleanor Williams edited their review of gene: PDE6D: Changed rating: RED; Changed publications: 24166846, 30423442; Changed phenotypes: ?Joubert syndrome 22, 615665; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.19 PDE6D Eleanor Williams commented on gene: PDE6D
Fetal anomalies v1.73 COL3A1 Rhiannon Mellis gene: COL3A1 was added
gene: COL3A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COL3A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COL3A1 were set to PMID: 28258187; 28742248; 25205403; 27168972; 24922459
Phenotypes for gene: COL3A1 were set to HP:0002126; HP:0001883; HP:0006496
Penetrance for gene: COL3A1 were set to Incomplete
Review for gene: COL3A1 was set to GREEN
Added comment: On OMIM COL3A1 has a polymicrogyria phenotype in the biallelic form, as well as talipes and other features (PMID: 28258187; PMID: 28742248; PMID: 25205403). No specifically prenatal reports of polymicrogyria in the literature but this feature would be detectable on fetal US and especially on fetal MRI.

A monoallelic COL3A1 variant has been reported in one case in a prenatal exome series (PMID: 27168972), causing EDS IV with a prenatal phenotype of forearm hypoplasia and phalangeal defects. PMID: 24922459 evidences that limb hypoplasia/limb reduction is observed in a small subset of EDS IV patients (5 unrelated cases), as well as talipes in a larger number, and occasionally facial clefts – all of which would be prenatally detectable features.
Sources: Literature
Intellectual disability v3.101 ALG14 Sarah Leigh commented on gene: ALG14: Have added the "for review" tag, to address the phenotypic variability of published carriers of ALG14 variants.
Intellectual disability v3.101 ALG14 Sarah Leigh Classified gene: ALG14 as Green List (high evidence)
Intellectual disability v3.101 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Intellectual disability v3.101 ALG14 Sarah Leigh Gene: alg14 has been classified as Green List (High Evidence).
Intellectual disability v3.100 ALG14 Sarah Leigh Tag for-review tag was added to gene: ALG14.
Renal ciliopathies v1.19 NEK1 Eleanor Williams commented on gene: NEK1
Intellectual disability v3.100 CNOT3 Sarah Leigh commented on gene: CNOT3
Intellectual disability v3.100 ALG14 Sarah Leigh Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates, MIM#616227; Intellectual disability to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual disability
Renal ciliopathies v1.19 KIAA0556 Eleanor Williams Publications for gene: KIAA0556 were set to
Renal ciliopathies v1.18 KIAA0556 Eleanor Williams Classified gene: KIAA0556 as Red List (low evidence)
Renal ciliopathies v1.18 KIAA0556 Eleanor Williams Added comment: Comment on list classification: Although there is evidence in that this variants in this gene are associated with Jouberts Syndrome there does not seem to be a strong renal phenotype, so leaving this gene rated as red for now.
Renal ciliopathies v1.18 KIAA0556 Eleanor Williams Gene: kiaa0556 has been classified as Red List (Low Evidence).
Renal ciliopathies v1.17 KIAA0556 Eleanor Williams commented on gene: KIAA0556
Renal ciliopathies v1.17 IFT27 Eleanor Williams commented on gene: IFT27
Renal ciliopathies v1.17 IFT27 Eleanor Williams Publications for gene: IFT27 were set to
Unexplained kidney failure in young people v1.89 VIPAS39 Eleanor Williams Tag for-review tag was added to gene: VIPAS39.
Tubulointerstitial kidney disease v1.9 SEC61A1 Eleanor Williams Tag for-review tag was added to gene: SEC61A1.
Tubulointerstitial kidney disease v1.9 DNAJB11 Eleanor Williams Tag for-review tag was added to gene: DNAJB11.
Renal tubulopathies v2.13 SLC2A2 Eleanor Williams Tag for-review tag was added to gene: SLC2A2.
Renal tubulopathies v2.13 HNF4A Eleanor Williams Tag for-review tag was added to gene: HNF4A.
Renal tubulopathies v2.13 CLDN10 Eleanor Williams Tag for-review tag was added to gene: CLDN10.
Fetal anomalies v1.73 ASXL3 Suzanne Drury commented on gene: ASXL3
Fetal anomalies v1.73 SHROOM4 Suzanne Drury gene: SHROOM4 was added
gene: SHROOM4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SHROOM4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SHROOM4 were set to 32565546
Phenotypes for gene: SHROOM4 were set to HP:0001274
Review for gene: SHROOM4 was set to AMBER
Added comment: Reported in fetal case series of abnormal corpus callosum PMID:32565546. Case also had Blake's pouch cyst, Turner syndrome: mos46,X, psu idic(X)(p11.2)[19/45,X[6]
Sources: Literature
Renal ciliopathies v1.16 IFT172 Eleanor Williams Tag for-review tag was added to gene: IFT172.
Renal ciliopathies v1.16 IFT140 Eleanor Williams Tag for-review tag was added to gene: IFT140.
Renal ciliopathies v1.16 ARMC9 Eleanor Williams Tag for-review tag was added to gene: ARMC9.
Nephrocalcinosis or nephrolithiasis v2.13 HNF4A Eleanor Williams Tag for-review tag was added to gene: HNF4A.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.11 CFB Eleanor Williams Tag for-review tag was added to gene: CFB.
Hereditary systemic amyloidosis v1.7 NLRP3 Eleanor Williams Tag for-review tag was added to gene: NLRP3.
Proteinuric renal disease v2.26 TPRKB Eleanor Williams Tag for-review tag was added to gene: TPRKB.
Proteinuric renal disease v2.26 CD151 Eleanor Williams Tag for-review tag was added to gene: CD151.
Proteinuric renal disease v2.26 AMN Eleanor Williams Tag for-review tag was added to gene: AMN.
Proteinuric renal disease v2.26 APOE Eleanor Williams Tag for-review tag was added to gene: APOE.
Proteinuric renal disease v2.26 DGKE Eleanor Williams Tag for-review tag was added to gene: DGKE.
Proteinuric renal disease v2.26 FN1 Eleanor Williams Phenotypes for gene: FN1 were changed from Glomerulopathy with fibronectin deposits 2, MIM# 601894 to Glomerulopathy with fibronectin deposits 2, 601894
Proteinuric renal disease v2.25 FN1 Eleanor Williams Publications for gene: FN1 were set to 18268355
Proteinuric renal disease v2.24 FN1 Eleanor Williams Classified gene: FN1 as Green List (high evidence)
Proteinuric renal disease v2.24 FN1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to green. More than 3 unrelated cases with FN1 variants reported in patients with Glomerulopathy with Fibronectin Deposits, which has proteinuria as a feature.
Proteinuric renal disease v2.24 FN1 Eleanor Williams Gene: fn1 has been classified as Green List (High Evidence).
Proteinuric renal disease v2.23 FN1 Eleanor Williams Tag for-review tag was added to gene: FN1.
Proteinuric renal disease v2.23 FN1 Eleanor Williams reviewed gene: FN1: Rating: ; Mode of pathogenicity: None; Publications: 18268355, 27056061, 31419955; Phenotypes: Glomerulopathy with Fibronectin Deposits 2, 601894; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v1.58 ABO Arina Puzriakova reviewed gene: ABO: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Virus susceptibility; Mode of inheritance: Unknown
Congenital muscular dystrophy v2.4 MYMK Zornitza Stark reviewed gene: MYMK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Carey-Fineman-Ziter syndrome (MIM #254940); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.4 FHL1 Zornitza Stark reviewed gene: FHL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19181672, 19171836; Phenotypes: Reducing body myopathy, X-linked 1a, severe, infantile or early childhood onset, MIM# 300717; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital muscular dystrophy v2.4 DPM1 Zornitza Stark reviewed gene: DPM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23856421, 16641202, 10642602, 10642597; Phenotypes: Congenital disorder of glycosylation, type Ie 608799; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.99 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.99 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.98 PIGK Sarah Leigh Deleted their comment
Intellectual disability v3.98 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Added comment: Comment on list classification: Zornitza Stark loaded PIGK as a green gene on Intellectual disability (https://panelapp.genomicsengland.co.uk/panels/285/gene/PIGK/#!review). and suggested that it was also suitable for the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Intellectual disability v3.97 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Early onset or syndromic epilepsy v2.94 PIGK Sarah Leigh gene: PIGK was added
gene: PIGK was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGK were set to 32220290
Phenotypes for gene: PIGK were set to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Review for gene: PIGK was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 7 variants reported in at least 5 unrelated cases with seizures.
Sources: Expert list
Intellectual disability v3.96 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Intellectual disability v3.96 PIGK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 10 variants reported in at least 9 unrelated cases.
Intellectual disability v3.96 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Intellectual disability v3.95 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.95 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Intellectual disability v3.95 PIGK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 10 variants reported in at least 9 unrelated cases.
Intellectual disability v3.95 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Intellectual disability v3.94 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.93 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Intellectual disability v3.92 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Intellectual disability; seizures; cerebellar atrophy to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Glaucoma (developmental) v1.8 SPATA13 Eleanor Williams changed review comment from: PMID: 32339198 Waseem et al report 1 large UK family and 8 unrelated individuals with variants in SPATA13 and primary angle-closure glaucoma. This is sufficient to rate this gene green for the disease association, however as the disease is adult-onset in these patients it is not appropriate to rate it green on this panel.
Sources: Literature; to: PMID: 32339198 Waseem et al report 1 large UK family and 8 unrelated individuals with variants in SPATA13 and primary angle-closure glaucoma. This is sufficient to rate this gene green for the disease association, however as the disease is adult-onset in these patients it is not appropriate to rate it green on this panel. Adding as red on advice of Genomics England Clinical team so that it will be reviewed if the scope of the panel changes in future.
Sources: Literature
Structural eye disease v1.9 SPATA13 Eleanor Williams Tag adult-onset tag was added to gene: SPATA13.
Structural eye disease v1.9 SPATA13 Eleanor Williams gene: SPATA13 was added
gene: SPATA13 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: SPATA13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPATA13 were set to 32339198
Phenotypes for gene: SPATA13 were set to primary angle-closure glaucoma
Review for gene: SPATA13 was set to RED
Added comment: PMID: 32339198 Waseem et al report 1 large UK family and 8 unrelated individuals with variants in SPATA13 and primary angle-closure glaucoma. This is sufficient to rate this gene green for the disease association, however as the disease is adult-onset in these patients it is not appropriate to rate it green on this panel. Adding as red on advice of Genomics England Clinical team so that it will be reviewed if the scope of the panel changes in future.
Sources: Literature
Glaucoma (developmental) v1.8 SPATA13 Eleanor Williams changed review comment from: PMID: 32339198 Waseem et al report 1 large UK family and 8 unrelated individuals with variants in SPATA13 and primary angle-closure glaucoma. This is sufficient to rate this gene green for the disease association, however as the disease is adult-onset nature in these patients it is not appropriate to rate it green on this panel.
Sources: Literature; to: PMID: 32339198 Waseem et al report 1 large UK family and 8 unrelated individuals with variants in SPATA13 and primary angle-closure glaucoma. This is sufficient to rate this gene green for the disease association, however as the disease is adult-onset in these patients it is not appropriate to rate it green on this panel.
Sources: Literature
Glaucoma (developmental) v1.8 SPATA13 Eleanor Williams Tag adult-onset tag was added to gene: SPATA13.
Glaucoma (developmental) v1.8 SPATA13 Eleanor Williams gene: SPATA13 was added
gene: SPATA13 was added to Glaucoma (developmental). Sources: Literature
Mode of inheritance for gene: SPATA13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPATA13 were set to 32339198
Phenotypes for gene: SPATA13 were set to Primary Angle Closure Glaucoma
Review for gene: SPATA13 was set to RED
Added comment: PMID: 32339198 Waseem et al report 1 large UK family and 8 unrelated individuals with variants in SPATA13 and primary angle-closure glaucoma. This is sufficient to rate this gene green for the disease association, however as the disease is adult-onset nature in these patients it is not appropriate to rate it green on this panel.
Sources: Literature
Inherited white matter disorders v1.76 SLC25A4 Sarah Leigh Added comment: Comment on mode of inheritance: At least two cases of white matter lesions have been reported with de novo variants in SLC25A4 (PMID 12112115; 27693233).
Inherited white matter disorders v1.76 SLC25A4 Sarah Leigh Mode of inheritance for gene: SLC25A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited white matter disorders v1.76 SLC25A4 Sarah Leigh Publications for gene: SLC25A4 were set to 25655951; 27693233; 30013777; 12112115
Inherited white matter disorders v1.75 SLC25A4 Sarah Leigh Publications for gene: SLC25A4 were set to 25655951; 27693233; 30013777
Inherited white matter disorders v1.74 SLC25A4 Sarah Leigh Phenotypes for gene: SLC25A4 were changed from Mitochondrial Leukoencephalopathy to Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD 617184; Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR 615418; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 609283
Inherited white matter disorders v1.73 SLC25A4 Sarah Leigh Publications for gene: SLC25A4 were set to 25655951; 27693233
Inherited white matter disorders v1.72 SLC25A4 Sarah Leigh Publications for gene: SLC25A4 were set to Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_578; PMID: 27693233
Undiagnosed metabolic disorders v1.416 SLC25A4 Sarah Leigh Added comment: Comment on mode of inheritance: Because Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR 615418 is also relevant to this panel.
Undiagnosed metabolic disorders v1.416 SLC25A4 Sarah Leigh Mode of inheritance for gene: SLC25A4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.3 FDXR Sara Martins reviewed gene: FDXR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30250212, PMID: 28965846, PMID: 29040572; Phenotypes: Auditory neuropathy and optic atrophy (MIM 617717); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.12 ISCU Sarah Leigh changed review comment from: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded here.; to: Comment on mode of inheritance: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant missense p.G97V variant has been reported and therefore this may represent a specific mechanism of action. Further evidence is needed to determine which (if any) other monoallelic variants will cause disease beyond mitochondrial myopathy, which justifies the mode of inheritance recorded.
Likely inborn error of metabolism v2.12 ISCU Sarah Leigh changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Rhabdomyolysis and metabolic muscle disorders v1.42 ISCU Sarah Leigh Added comment: Comment on mode of inheritance: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant missense p.G97V variant has been reported and therefore this may represent a specific mechanism of action. Further evidence is needed to determine which (if any) other monoallelic variants will cause disease beyond mitochondrial myopathy, which justifies the mode of inheritance recorded.
Rhabdomyolysis and metabolic muscle disorders v1.42 ISCU Sarah Leigh Mode of inheritance for gene: ISCU was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.41 ISCU Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.415 ISCU Sarah Leigh changed review comment from: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.; to: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant missense p.G97V variant has been reported and therefore this may represent a specific mechanism of action. Further evidence is needed to determine which (if any) other monoallelic variants will cause disease beyond mitochondrial myopathy, which justifies the mode of inheritance recorded.
Undiagnosed metabolic disorders v1.415 ISCU Sarah Leigh Added comment: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.
Undiagnosed metabolic disorders v1.415 ISCU Sarah Leigh Mode of inheritance for gene: ISCU was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.41 ISCU Sarah Leigh Publications for gene: ISCU were set to 21165651; 22125086
Rhabdomyolysis and metabolic muscle disorders v1.40 ISCU Sarah Leigh Added comment: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.
Rhabdomyolysis and metabolic muscle disorders v1.40 ISCU Sarah Leigh Mode of inheritance for gene: ISCU was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.3 MECR Sara Martins reviewed gene: MECR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27817865, PMID: 31137067; Phenotypes: Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.3 CAPN15 Eleanor Williams Tag watchlist tag was added to gene: CAPN15.
Bilateral congenital or childhood onset cataracts v2.3 CAPN15 Eleanor Williams commented on gene: CAPN15
Structural eye disease v1.8 CAPN15 Eleanor Williams Tag watchlist tag was added to gene: CAPN15.
Monogenic hearing loss v2.19 USP48 Eleanor Williams Tag watchlist tag was added to gene: USP48.
Intellectual disability v3.91 SCAF4 Eleanor Williams Tag watchlist tag was added to gene: SCAF4.
CAKUT v1.152 DACT1 Eleanor Williams Tag watchlist tag was added to gene: DACT1.
CAKUT v1.152 FOXD2 Eleanor Williams Tag watchlist tag was added to gene: FOXD2.
Intellectual disability v3.91 SATB1 Eleanor Williams Tag watchlist tag was added to gene: SATB1.
Optic neuropathy v2.3 AFG3L2 Sara Martins reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32219868; Phenotypes: Spastic ataxia 5, autosomal recessive (MIM#614487), Spinocerebellar ataxia 28 (MIM#610246); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital disorders of glycosylation v2.10 GALNT2 Sarah Leigh Classified gene: GALNT2 as Green List (high evidence)
Congenital disorders of glycosylation v2.10 GALNT2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Congenital disorders of glycosylation v2.10 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Green List (High Evidence).
Congenital disorders of glycosylation v2.9 GALNT2 Sarah Leigh Classified gene: GALNT2 as Green List (high evidence)
Congenital disorders of glycosylation v2.9 GALNT2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Congenital disorders of glycosylation v2.9 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Green List (High Evidence).
Congenital disorders of glycosylation v2.8 GALNT2 Sarah Leigh Publications for gene: GALNT2 were set to 32293671
Congenital disorders of glycosylation v2.7 GALNT2 Sarah Leigh Phenotypes for gene: GALNT2 were changed from Congenital disorder of glycosylation to Congenital disorder of glycosylation, type IIt 618885
Glycogen storage disease v1.4 PYGM Sarah Leigh Publications for gene: PYGM were set to 20301518
Severe microcephaly v2.8 TMX2 Sarah Leigh Classified gene: TMX2 as Green List (high evidence)
Severe microcephaly v2.8 TMX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Primary microcephaly, cortical malformation and epileptic encephalopathy. At least 7 variants reported in at least 9 unrelated cases of Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity 618730 (PMID 31735293; 31270415).
Severe microcephaly v2.8 TMX2 Sarah Leigh Gene: tmx2 has been classified as Green List (High Evidence).
Malformations of cortical development v2.7 TMX2 Sarah Leigh Classified gene: TMX2 as Green List (high evidence)
Malformations of cortical development v2.7 TMX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Primary microcephaly, cortical malformation and epileptic encephalopathy. At least 7 variants reported in at least 9 unrelated cases of Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity 618730 (PMID 31735293; 31270415).
Malformations of cortical development v2.7 TMX2 Sarah Leigh Gene: tmx2 has been classified as Green List (High Evidence).
Severe microcephaly v2.7 TMX2 Sarah Leigh gene: TMX2 was added
gene: TMX2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31735293; 31270415
Phenotypes for gene: TMX2 were set to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity 618730
Review for gene: TMX2 was set to GREEN
Added comment: Sources: Literature
Malformations of cortical development v2.6 TMX2 Sarah Leigh gene: TMX2 was added
gene: TMX2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31735293; 31270415
Phenotypes for gene: TMX2 were set to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity 618730
Review for gene: TMX2 was set to GREEN
Added comment: Sources: Literature
Cerebellar hypoplasia v1.41 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Cerebellar hypoplasia v1.41 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Cerebellar hypoplasia v1.41 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.10 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Limb disorders v2.10 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Limb disorders v2.10 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.9 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Limb disorders. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Cerebellar hypoplasia v1.40 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Cerebellar hypoplasia. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Congenital muscular dystrophy v2.4 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: RED; Mode of pathogenicity: None; Publications: 31469168, 31266720, 28803818; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 612937; Mode of inheritance: None
Congenital muscular dystrophy v2.4 CAVIN1 Zornitza Stark gene: CAVIN1 was added
gene: CAVIN1 was added to Congenital muscular dystrophy. Sources: Expert list
Mode of inheritance for gene: CAVIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAVIN1 were set to 19726876; 12116229
Phenotypes for gene: CAVIN1 were set to Lipodystrophy, congenital generalized, type 4 (MIM#613327)
Review for gene: CAVIN1 was set to GREEN
gene: CAVIN1 was marked as current diagnostic
Added comment: Muscular dystrophy as well as lipodystrophy.
Sources: Expert list
Leber hereditary optic neuropathy v1.4 DNAJC30 Eleanor Williams gene: DNAJC30 was added
gene: DNAJC30 was added to Leber hereditary optic neuropathy. Sources: Literature
watchlist tags were added to gene: DNAJC30.
Mode of inheritance for gene: DNAJC30 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAJC30 were set to Leber hereditary optic neuropathy
Review for gene: DNAJC30 was set to RED
Added comment: ESHG 2020 conference presentation - C25.5 - Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy - Sarah Stenton et al. Report 29 families with individuals with biallelic variants in DNAJC30 and a Leber's hereditary optic neuropathy. 27 of the families have the same p.Tyr51Cys variant and come from Eastern Europe. Analysis suggests a founder mutation from 85 generations agao. 2 other variants found in other families p.Pro78Ser and p.Leu101Gln. Pentrance is not complete.
No publication relating to this work is found in PubMed at this time.
Sources: Literature
Adult onset leukodystrophy v1.4 SPG21 Zornitza Stark gene: SPG21 was added
gene: SPG21 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: SPG21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPG21 were set to 14564668
Phenotypes for gene: SPG21 were set to Mast syndrome, MIM# 248900
Review for gene: SPG21 was set to GREEN
Added comment: Three patients reported with white matter abnormalities, diagnosed with Mast syndrome.
Sources: Expert list
Adult onset leukodystrophy v1.4 RPS6KA3 Zornitza Stark reviewed gene: RPS6KA3: Rating: RED; Mode of pathogenicity: None; Publications: 16691578; Phenotypes: Coffin-Lowry syndrome MIM#303600; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset leukodystrophy v1.4 RNF216 Zornitza Stark reviewed gene: RNF216: Rating: AMBER; Mode of pathogenicity: None; Publications: 28334938, 26250479; Phenotypes: Cerebellar ataxia and hypogonadotropic hypogonadism MIM#212840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.4 RNASET2 Zornitza Stark reviewed gene: RNASET2: Rating: RED; Mode of pathogenicity: None; Publications: 19525954; Phenotypes: Leukoencephalopathy, cystic, without megalencephaly, MIM# 612951; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.4 POLR1C Zornitza Stark reviewed gene: POLR1C: Rating: AMBER; Mode of pathogenicity: None; Publications: 26151409, 32042905; Phenotypes: Leukodystrophy, hypomyelinating, 11, MIM# 616494; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.4 OCRL Zornitza Stark reviewed gene: OCRL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lowe syndrome, MIM# 309000; Mode of inheritance: None
Adult onset leukodystrophy v1.4 NPC1 Zornitza Stark gene: NPC1 was added
gene: NPC1 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPC1 were set to 26910362; 29406968
Phenotypes for gene: NPC1 were set to Niemann-Pick disease, type C1/D 257220
Review for gene: NPC1 was set to GREEN
gene: NPC1 was marked as current diagnostic
Added comment: White matter lesions identified in MRI of 5/11 of Niemann-Pick patients (including adult-onset) and in an NPC mouse model.
Sources: Expert list
Adult onset leukodystrophy v1.4 MARS Zornitza Stark reviewed gene: MARS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2U MIM#616280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.4 MAN2B1 Zornitza Stark gene: MAN2B1 was added
gene: MAN2B1 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: MAN2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MAN2B1 were set to Mannosidosis, alpha-, types I and II, MIM# 248500
Review for gene: MAN2B1 was set to GREEN
gene: MAN2B1 was marked as current diagnostic
Added comment: White matter changes may occur in adulthood.
Sources: Expert list
Adult onset leukodystrophy v1.4 HMGCL Zornitza Stark reviewed gene: HMGCL: Rating: RED; Mode of pathogenicity: None; Publications: 28583327; Phenotypes: HMG-CoA lyase deficiency, MIM# 246450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.4 GCDH Zornitza Stark gene: GCDH was added
gene: GCDH was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GCDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCDH were set to 15985591
Phenotypes for gene: GCDH were set to Glutaric aciduria, type I 231670
Review for gene: GCDH was set to AMBER
Added comment: Two unrelated individuals reported with late-onset neurological disease including leukodystrophy. Note typical GA Type I has onset before the age of 2 years, and leukodystrophy is not a prominent feature.
Sources: Expert list
Adult onset leukodystrophy v1.4 EPRS Zornitza Stark gene: EPRS was added
gene: EPRS was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 29576217
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15, MIM# 617951
Review for gene: EPRS was set to GREEN
gene: EPRS was marked as current diagnostic
Added comment: Four unrelated families reported with this neurodegenerative disorder. Onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, dysphagia, severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum.
Sources: Expert list
Adult onset leukodystrophy v1.4 EARS2 Zornitza Stark reviewed gene: EARS2: Rating: RED; Mode of pathogenicity: None; Publications: 22492562, 23008233, 25854774, 26619324, 26893310; Phenotypes: Combined oxidative phosphorylation deficiency 12, MIM# 614924, Leukoencephalopathy with thalamus and brainstem involvement and high lactate; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.4 CYP7B1 Zornitza Stark gene: CYP7B1 was added
gene: CYP7B1 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: CYP7B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP7B1 were set to 24117163; 19439420; 19187859
Phenotypes for gene: CYP7B1 were set to Spastic paraplegia 5A, autosomal recessive, MIM# 270800
Review for gene: CYP7B1 was set to GREEN
gene: CYP7B1 was marked as current diagnostic
Added comment: White matter lesions have been reported as a feature of the condition in >3 cases.
Sources: Expert list
Adult onset leukodystrophy v1.4 CTC1 Zornitza Stark reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 22267198, 22387016, 22532422; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset leukodystrophy v1.4 COL4A2 Zornitza Stark reviewed gene: COL4A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 2, MIM# 614483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset leukodystrophy v1.4 AUH Zornitza Stark gene: AUH was added
gene: AUH was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: AUH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AUH were set to 20855850
Phenotypes for gene: AUH were set to 3-methylglutaconic aciduria, type I, MIM# 250950
Review for gene: AUH was set to GREEN
gene: AUH was marked as current diagnostic
Added comment: Onset is typically in childhood, though presentation is variable so we have this gene on both paediatric and adult panels. Specifically, two individuals with late onset disease including leukodystrophy reported.
Sources: Expert list
Adult onset leukodystrophy v1.4 ASPA Zornitza Stark gene: ASPA was added
gene: ASPA was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: ASPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASPA were set to Canavan disease, MIM# 271900
Review for gene: ASPA was set to GREEN
Added comment: Congenital, infantile, and late-onset forms of Canavan disease reported.
Sources: Expert list
Adult onset leukodystrophy v1.4 AARS Zornitza Stark reviewed gene: AARS: Rating: AMBER; Mode of pathogenicity: None; Publications: 31775912; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2N 613287; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.93 DDC Lothar Schlueter edited their review of gene: DDC: Changed publications: 28100251, 30952622, 20505134, 19172410, 32369189, 18754761, 32409695
Early onset or syndromic epilepsy v2.93 DDC Lothar Schlueter changed review comment from: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures.
Sources: Literature; to: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures. In recent cohort analysis they concluded that about 30% of AADCD patients have been initially diagnosed with epilepsy (Pearson et al.2020, Wen et al. 2020)
Sources: Literature

Update: Added more literature
Amelogenesis imperfecta v2.8 DLX3 Eleanor Williams changed review comment from: Comment on phenotypes: Adding phenotype of Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic to this gene at suggestion of Dr Susan Parekh (Consultant in Pediatric Dentistry, GOSH); to: Comment on phenotypes: Adding phenotype of Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic to this gene at suggestion of Dr Susan Parekh (Consultant in Pediatric Dentistry, GOSH)
CAKUT v1.152 CHD1L Zornitza Stark edited their review of gene: CHD1L: Added comment: Re-evaluation in light of population data: the 6 missense variants reported in the two papers (PMID: 22146311, 24429398) are very common in gnomAD: CHD1L:c.2098G>A; p.Gly700Arg - 1110 hets, 5 hom CHD1L:c.2295A>G; p.Ile765Met - 468 hets, 1 hom CHD1L:c.2479A>G; p.Ile827Val – 725 hets, 2 hom CHD1L:c.998C>G; p.Pro333Arg – 1 het, 0 hom CHD1L:c.1199A>G; p.Glu400Gly – 3 hets, 0 hom CHD1L:c.1551A>G; p.Ile517Met – 195 hets, 0 hom I could not find any other papers for this gene in association with CAKUT. ClinVar only has 1 frameshift variant reported as pathogenic from research in 2001 for an unrelated condition (short stature), the other variants reported in this gene are VUS or LB/B. These population variant frequencies are out of keeping for a Mendelian disorder.; Changed rating: RED; Changed publications: 22146311, 24429398
Rare anaemia v1.4 RPL26 Ivone Leong Tag for-review tag was added to gene: RPL26.
Rare anaemia v1.4 COX4I2 Ivone Leong Tag for-review tag was added to gene: COX4I2.
Adult solid tumours cancer susceptibility v2.4 DGCR8 Ivone Leong Classified gene: DGCR8 as Red List (low evidence)
Adult solid tumours cancer susceptibility v2.4 DGCR8 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Added as a Red gene.
Adult solid tumours cancer susceptibility v2.4 DGCR8 Ivone Leong Gene: dgcr8 has been classified as Red List (Low Evidence).
COVID-19 research v1.58 ABO Eleanor Williams changed review comment from: Preprint https://doi.org/10.1101/2020.06.07.20124610.t Pourali et al 2020 - meta-analysis of blood group and risk of infect ion and death in COVID-19. Supports the finding that those with blood group A are at higher risk for COVID-19 infection while those with blood group O are at lower risk.; to: Preprint https://doi.org/10.1101/2020.06.07.20124610 Pourali et al 2020 - meta-analysis of blood group and risk of infect ion and death in COVID-19. Supports the finding that those with blood group A are at higher risk for COVID-19 infection while those with blood group O are at lower risk.
COVID-19 research v1.58 ABO Eleanor Williams commented on gene: ABO
COVID-19 research v1.58 CH25H Eleanor Williams gene: CH25H was added
gene: CH25H was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: CH25H was set to Unknown
Review for gene: CH25H was set to RED
Added comment: Preprint: https://doi.org/10.1101/2020.06.08.141077 Zang et al 2020 - identified
CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of
virus replication using in-vitro assays.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.12 ARL6IP1 Zornitza Stark reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 31272422, 30980493, 28471035; Phenotypes: Spastic paraplegia 61, autosomal recessive, MIM#615685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
COVID-19 research v1.57 TRIM69 Sarah Leigh Classified gene: TRIM69 as Red List (low evidence)
COVID-19 research v1.57 TRIM69 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PMID 22105173 reports three TRIM69 variants in three cases who had had herpes simplex encephalitis during childhood. Evidence for was strong for the homozygous p.R141*, but less so for the heterozygous p.S186L, which functional studies showed was hypomorphic and not a complete loss-of-function allele, possibly explaining variable penetrance in other carriers. The third variant p.P625L was not supported by functional studies and was also present in the unaffected father of the proband.
COVID-19 research v1.57 TRIM69 Sarah Leigh Gene: trim69 has been classified as Red List (Low Evidence).
Intellectual disability v3.91 WNT1 Catherine Snow Classified gene: WNT1 as Green List (high evidence)
Intellectual disability v3.91 WNT1 Catherine Snow Added comment: Comment on list classification: Identified by expert review from Zornitza Stark, sufficient number of unrelated patients for WNT1 to be classified as Green
Intellectual disability v3.91 WNT1 Catherine Snow Gene: wnt1 has been classified as Green List (High Evidence).
COVID-19 research v1.56 TNF Sarah Leigh Classified gene: TNF as Green List (high evidence)
COVID-19 research v1.56 TNF Sarah Leigh Added comment: Comment on list classification: Various publications demonstrating associations between TNF variants and viral infection susceptibility and progression.
COVID-19 research v1.56 TNF Sarah Leigh Gene: tnf has been classified as Green List (High Evidence).
COVID-19 research v1.55 TNF Sarah Leigh Mode of inheritance for gene: TNF was changed from to Unknown
COVID-19 research v1.54 IFNG Sarah Leigh Classified gene: IFNG as Green List (high evidence)
COVID-19 research v1.54 IFNG Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Two promoter variants are associated with viral susceptibility and response to therapy; c.-179G>T (RCV000015845.26) with accelerated progression to AIDS (PMID 12854077) and c.-764C>G (rs2069707) with enhanced promoter activity and increased viral clearance and treatment response in hepatitis C virus infection (PMID 17215375). The A allele of rs2430561 is associate with susceptibility to Hepatitis B virus infection (PMID 26458193).
COVID-19 research v1.54 IFNG Sarah Leigh Gene: ifng has been classified as Green List (High Evidence).
COVID-19 research v1.53 IFNG Sarah Leigh Phenotypes for gene: IFNG were changed from {AIDS, rapid progression to} 609423 to {AIDS, rapid progression to} 609423; {Hepatitis C virus, response to therapy of} 609532
COVID-19 research v1.52 IFNG Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients.
From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans.
PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups.
; to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 17981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients.
From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans.
PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups.
COVID-19 research v1.52 IFNG Sarah Leigh Publications for gene: IFNG were set to 178981204; 17215375; 12854077; 26458193
Hereditary neuropathy v1.368 TRPA1 Tracy Lester reviewed gene: TRPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 20547126, 25724085; Phenotypes: episodic debilitating upper body pain triggered by fasting, cold and physical stress; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v1.51 FUT2 Sarah Leigh Mode of inheritance for gene: FUT2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v1.50 FUT2 Sarah Leigh Classified gene: FUT2 as Amber List (moderate evidence)
COVID-19 research v1.50 FUT2 Sarah Leigh Added comment: Comment on list classification: Variants in FUT2 are responsible for resistance to Norovirus infection in certain populations (PMID 30845670). This gene is Green on the Viral Resistance panel (https://panelapp.genomicsengland.co.uk/panels/928/gene/FUT2/#!review)
COVID-19 research v1.50 FUT2 Sarah Leigh Gene: fut2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.49 FUT2 Sarah Leigh Publications for gene: FUT2 were set to 30845670
Limb disorders v2.8 KYNU Eleanor Williams Tag for-review tag was added to gene: KYNU.
Limb disorders v2.8 KYNU Eleanor Williams Classified gene: KYNU as Green List (high evidence)
Limb disorders v2.8 KYNU Eleanor Williams Gene: kynu has been classified as Green List (High Evidence).
COVID-19 research v1.48 IRF4 Sarah Leigh Mode of inheritance for gene: IRF4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v1.47 IRF4 Sarah Leigh Publications for gene: IRF4 were set to
COVID-19 research v1.46 IL6 Sarah Leigh Phenotypes for gene: IL6 were changed from to {Kaposi sarcoma, susceptibility to} 148000
COVID-19 research v1.45 IL6 Sarah Leigh Publications for gene: IL6 were set to
COVID-19 research v1.44 IL6 Sarah Leigh Mode of inheritance for gene: IL6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v2.5 TNNI2 Zornitza Stark reviewed gene: TNNI2: Rating: RED; Mode of pathogenicity: None; Publications: 16924011; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.5 SLC25A42 Zornitza Stark reviewed gene: SLC25A42: Rating: AMBER; Mode of pathogenicity: None; Publications: 26541337, 29923093, 29327420; Phenotypes: Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression (MIM#618416); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.5 CASQ1 Zornitza Stark reviewed gene: CASQ1: Rating: RED; Mode of pathogenicity: None; Publications: 30258016, 25116801, 26136523; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates 616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v2.7 KYNU Eleanor Williams Classified gene: KYNU as Red List (low evidence)
Limb disorders v2.7 KYNU Eleanor Williams Added comment: Comment on list classification: Changing the rating from red to green as 3 unrelated cases have been reported with a distinct hand hyperphalangism phenotype and biallelic or compound heterozygous variants, and segregation as expected in the family in 2 cases (3rd could not be established).
Limb disorders v2.7 KYNU Eleanor Williams Gene: kynu has been classified as Red List (Low Evidence).
Limb disorders v2.6 KYNU Eleanor Williams gene: KYNU was added
gene: KYNU was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: KYNU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KYNU were set to 31923704
Phenotypes for gene: KYNU were set to Vertebral, cardiac, renal, and limb defects syndrome 2, 617661; hand hyperphalangism
Review for gene: KYNU was set to GREEN
Added comment: KYNU is associated with Vertebral, cardiac, renal, and limb defects syndrome 2 #617661 (AR) in OMIM.

PMID: 31923704 Ehmke et al 2020 - report 3 unrelated individuals with a ballelic or compound het (a deletion of axons 1-8 and a missense variant) in KYNU and a multisystemic syndrome with hand hyperphalangism resembling Catel-Manzke syndrome. Other features included heart defects and developmental delay (mild in 2 cases) and mild vertebral defects. Microretrognathia was observed in 2 patients consistent with Catel-Manzke syndrome. Two affected individuals tested had elevated urine xanthurenic acid.

PMID: 28792876 Shi et al 2017 - report 2 families where the proband is homozygous or compound heterozygous for loss of function variants in KUNU. The hyperphalgnism described by Ehmke et al was NOT seen, although one patient had talipes, syndactyly and rhizomelia and the other had shortened long bones. Both had cardiac, renal and defects in vertebral segmentation.
Sources: Literature
Congenital myopathy v2.5 CHCHD10 Zornitza Stark Deleted their review
Congenital myopathy v2.5 CHCHD10 Zornitza Stark reviewed gene: CHCHD10: Rating: AMBER; Mode of pathogenicity: None; Publications: 22818856, 25193783; Phenotypes: Congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.14 DYNC2H1 Eleanor Williams gene: DYNC2H1 was added
gene: DYNC2H1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: DYNC2H1 was set to BIALLELIC, autosomal or pseudoautosomal
Added comment: ESHG 2020 - Presentation/abstract - C06.5 - DYNC2H1 hypomorphic or retina-predominant variants cause non-syndromic retinal degeneration - Vig et al. Genome and exome sequencing were performed for 5 unrelated cases of inherited retinal disease with no identified variant. Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779 A>T; V3, g.103112272 C>G; V4, g.103070104 A>C) and one previously reported (V5, g.103339363 T>G) were identified. The variants were either hypomorphic or affect a retina-predominant transcript. First report of DYNC2H1 variants, causing non-syndromic IRD. 3 of the families from the UK shared the same homozygous variant (V3) - possible founder mutation in South Asias in the UK.
Note this gene produces a dynein-2 protein that is found in cilia.
No publication relating to this work has been found in PubMed at this time.
Sources: Literature
Intellectual disability v3.90 SCAF4 Eleanor Williams changed review comment from: ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature; to: Conference talk/abstract from ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature
Monogenic hearing loss v2.19 USP48 Eleanor Williams changed review comment from: ESHG2020 - C06.2 - Whole Exome Sequencing, Molecular Assays, Immunohistology and Animal Models associate USP48 to Hereditary Hearing Loss - Bassani et al. Report 1 large Italian family, and 2 unrelated Dutch families with non-syndromic hearing loss and potentially pathogenic missense variants in USP48. A 4th case with unilateral cochlear nerve aplasia and a de novo splice variant in the same gene is reported. A zebrafish knockout for the USP48 paralog showed delayed primary motoneurons development and behaviour indicative of vestibular dysfunction and hearing impairment and acoustic startle response assays revealed a reduced auditory response.
No publication relating to this work could be found in PubMed at this time.
Sources: Literature; to: Conference talk/abstract from ESHG2020 - C06.2 - Whole Exome Sequencing, Molecular Assays, Immunohistology and Animal Models associate USP48 to Hereditary Hearing Loss - Bassani et al. Report 1 large Italian family, and 2 unrelated Dutch families with non-syndromic hearing loss and potentially pathogenic missense variants in USP48. A 4th case with unilateral cochlear nerve aplasia and a de novo splice variant in the same gene is reported. A zebrafish knockout for the USP48 paralog showed delayed primary motoneurons development and behaviour indicative of vestibular dysfunction and hearing impairment and acoustic startle response assays revealed a reduced auditory response.
No publication relating to this work could be found in PubMed at this time.
Sources: Literature
Structural eye disease v1.8 CAPN15 Eleanor Williams changed review comment from: ESHG2020 - C06.4 - Mouse and human studies support a role for CAPN15 variants in cataract and microphthalmia - Zha et al. Describe a Capn15 mouse knockout with cataract and microphthalmia, and three human cases with phenotypes including growth delay (2/3), cataracts (1/3), coloboma (2/3) and microphthalmia (2/3). They were identified with homozygous or compound heterozygous likely pathogenic variants in CAPN15.
No publication relating to this work has been identified in PubMed at this time.
Sources: Literature; to: Conference talk/abstract from ESHG2020 - C06.4 - Mouse and human studies support a role for CAPN15 variants in cataract and microphthalmia - Zha et al. Describe a Capn15 mouse knockout with cataract and microphthalmia, and three human cases with phenotypes including growth delay (2/3), cataracts (1/3), coloboma (2/3) and microphthalmia (2/3). They were identified with homozygous or compound heterozygous likely pathogenic variants in CAPN15.
No publication relating to this work has been identified in PubMed at this time.
Sources: Literature
Structural eye disease v1.8 CAPN15 Eleanor Williams gene: CAPN15 was added
gene: CAPN15 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CAPN15 were set to Anophthalmia, microphthalmia and coloboma
Review for gene: CAPN15 was set to RED
Added comment: ESHG2020 - C06.4 - Mouse and human studies support a role for CAPN15 variants in cataract and microphthalmia - Zha et al. Describe a Capn15 mouse knockout with cataract and microphthalmia, and three human cases with phenotypes including growth delay (2/3), cataracts (1/3), coloboma (2/3) and microphthalmia (2/3). They were identified with homozygous or compound heterozygous likely pathogenic variants in CAPN15.
No publication relating to this work has been identified in PubMed at this time.
Sources: Literature
Monogenic hearing loss v2.19 USP48 Eleanor Williams gene: USP48 was added
gene: USP48 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: USP48 was set to Unknown
Phenotypes for gene: USP48 were set to non-syndromic hearing loss
Review for gene: USP48 was set to RED
Added comment: ESHG2020 - C06.2 - Whole Exome Sequencing, Molecular Assays, Immunohistology and Animal Models associate USP48 to Hereditary Hearing Loss - Bassani et al. Report 1 large Italian family, and 2 unrelated Dutch families with non-syndromic hearing loss and potentially pathogenic missense variants in USP48. A 4th case with unilateral cochlear nerve aplasia and a de novo splice variant in the same gene is reported. A zebrafish knockout for the USP48 paralog showed delayed primary motoneurons development and behaviour indicative of vestibular dysfunction and hearing impairment and acoustic startle response assays revealed a reduced auditory response.
No publication relating to this work could be found in PubMed at this time.
Sources: Literature
Intellectual disability v3.90 SCAF4 Eleanor Williams gene: SCAF4 was added
gene: SCAF4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added comment: ESHG2020 - C02.1 - SCAF4 loss of function in humans and Drosophila implicates mRNA transcriptional termination in neurodevelopmental disorders - Fliedner et al - report 9 unrelated patients with likely pathogenic variants in SCAF4 and mild developmental delay and intellectual disability. 8 de novo. 1 inherited. Seizures, skeletal, renal and cardiac anomalies were also seen.
Sources: Literature
Skeletal dysplasia v2.9 SOX9 Eleanor Williams commented on gene: SOX9: ESHG2020 - Poster E-PO1.34 Ledig et al Report a case of two sisters, 46XY, who are homozygous for a variant, c.1518C>G p.(Leu506Val), in SOX9. The sisters had a suspicion of non-syndromic XY DSD (disorder of sexual development) and no signs of skeletal malformations. By luciferase assay the variant reporte dhereshowed no decrease of transactivating function on Col2a1 promotor in contrast to two SOX9 mutations (c.347C>T p.(Ala116Val) and c.358C>T p.(Arg120Cys)) known to be associated with CD. The authors suggest that SOX9 variant c.1518C>G p.(Leu506Val) is a hypomorphic mutation that causes XY DSD without raising any SOX9 related skeletal phenotype.
No publication relating to this work could be found in PubMed at this time.
Amelogenesis imperfecta v2.8 SP6 Eleanor Williams Publications for gene: SP6 were set to 32167558
Amelogenesis imperfecta v2.7 SP6 Eleanor Williams Classified gene: SP6 as Amber List (moderate evidence)
Amelogenesis imperfecta v2.7 SP6 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber. 1 case plus rodent models reported.
Amelogenesis imperfecta v2.7 SP6 Eleanor Williams Gene: sp6 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v2.6 SP6 Eleanor Williams gene: SP6 was added
gene: SP6 was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: SP6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP6 were set to 32167558
Phenotypes for gene: SP6 were set to Amelogenesis Imperfecta
Review for gene: SP6 was set to AMBER
Added comment: PMID: 32167558 - Smith et al 2020 - report a 2 bp variant c.817_818GC>AA in SP6 in a Caucasian family with autosomal dominant hypoplastic AI which results in a missense change. Report that mice and rat knockouts also show a dental phenotype (PMID: 18156176, 18297738, 22676574 )
Sources: Literature
Long QT syndrome v2.16 KCNE1 Ivone Leong commented on gene: KCNE1: Penetrance for this gene has been changed from "complete" to "incomplete" based on PMID: 11692163 and also review from Claire Kirk (UCD).
Long QT syndrome v2.16 KCNE1 Ivone Leong Source South West GLH was removed from KCNE1.
Source London South GLH was removed from KCNE1.
Source North West GLH was removed from KCNE1.
Penetrance for gene KCNE1 was set from to Complete
Long QT syndrome v2.15 SCN5A Ivone Leong changed review comment from: Penetrance for this gene has been changed from "complete" to "incomplete" based on PMID: 9927399 and also review from Claire Kirk (UCD).; to: Penetrance for this gene has been changed from "complete" to "incomplete" based on PMID: 29728395 and also review from Claire Kirk (UCD).
Long QT syndrome v2.15 KCNE1 Ivone Leong Publications for gene: KCNE1 were set to 19716085; 31983240
Long QT syndrome v2.14 SCN5A Ivone Leong commented on gene: SCN5A: Penetrance for this gene has been changed from "complete" to "incomplete" based on PMID: 9927399 and also review from Claire Kirk (UCD).
Long QT syndrome v2.14 SCN5A Ivone Leong Source South West GLH was removed from SCN5A.
Source London South GLH was removed from SCN5A.
Source North West GLH was removed from SCN5A.
Phenotypes for gene: SCN5A were changed from Ventricular fibrillation, familial, 1 (603829); Brugada syndrome 1 (601144); Heart block, nonprogressive (113900); Heart block, progressive, type IA (113900); {Sudden infant death syndrome, susceptibility to} (272120); Sick sinus syndrome 1 (608567); Long QT syndrome-3 ; Long QT syndrome-3 (603830); Cardiomyopathy, dilated, 1E (601154); Atrial fibrillation, familial, 10 (614022) to Ventricular fibrillation, familial, 1 (603829); Brugada syndrome 1 (601144); Heart block, nonprogressive (113900); Heart block, progressive, type IA (113900); {Sudden infant death syndrome, susceptibility to} (272120); Sick sinus syndrome 1 (608567); Long QT syndrome-3; Long QT syndrome-3 (603830); Cardiomyopathy, dilated, 1E (601154); Atrial fibrillation, familial, 10 (614022)
Penetrance for gene SCN5A was set from to Complete
Long QT syndrome v2.13 SCN5A Ivone Leong Publications for gene: SCN5A were set to 19716085; 29798782; 26888179; 7889574
Long QT syndrome v2.12 KCNQ1 Ivone Leong Publications for gene: KCNQ1 were set to 19716085; 26888179; 8528244
Long QT syndrome v2.11 KCNH2 Ivone Leong Publications for gene: KCNH2 were set to 19716085; 31358886; 26888179; 7889573
Long QT syndrome v2.10 KCNH2 Ivone Leong commented on gene: KCNH2: Penetrance for this gene has been changed from "complete" to "incomplete" based on PMID: 9927399 and also review from Claire Kirk (UCD).
Long QT syndrome v2.10 KCNH2 Ivone Leong Source South West GLH was removed from KCNH2.
Source London South GLH was removed from KCNH2.
Source North West GLH was removed from KCNH2.
Penetrance for gene KCNH2 was set from to Complete
Long QT syndrome v2.9 KCNQ1 Ivone Leong edited their review of gene: KCNQ1: Added comment: Penetrance for this gene has been changed from "complete" to "incomplete" based on PMID: 9927399 and also review from Claire Kirk (UCD).; Changed publications: 9927399
Long QT syndrome v2.9 KCNQ1 Ivone Leong Source South West GLH was removed from KCNQ1.
Source London South GLH was removed from KCNQ1.
Source North West GLH was removed from KCNQ1.
Penetrance for gene KCNQ1 was set from to Complete
Long QT syndrome v2.8 TRDN Ivone Leong Classified gene: TRDN as Green List (high evidence)
Long QT syndrome v2.8 TRDN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene has been given a Green status based on the evidence, which supports a gene-disease association.
Long QT syndrome v2.8 TRDN Ivone Leong Gene: trdn has been classified as Green List (High Evidence).
Long QT syndrome v2.7 KCNE2 Ivone Leong Tag for-review tag was added to gene: KCNE2.
Long QT syndrome v2.7 KCNE1 Ivone Leong Tag for-review tag was added to gene: KCNE1.
Long QT syndrome v2.7 KCNE1 Ivone Leong Publications for gene: KCNE1 were set to 19716085
COVID-19 research v1.43 CX3CR1 Sarah Leigh Classified gene: CX3CR1 as Amber List (moderate evidence)
COVID-19 research v1.43 CX3CR1 Sarah Leigh Gene: cx3cr1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.42 CX3CR1 Sarah Leigh Mode of inheritance for gene: CX3CR1 was changed from to BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v1.41 CPT2 Sarah Leigh Classified gene: CPT2 as Amber List (moderate evidence)
COVID-19 research v1.41 CPT2 Sarah Leigh Gene: cpt2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.40 CPT2 Sarah Leigh Mode of inheritance for gene: CPT2 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v1.39 CD209 Sarah Leigh Phenotypes for gene: CD209 were changed from to {Dengue fever, protection against} 614371; {HIV type 1, susceptibility to} 609423; {Mycobacterium tuberculosis, susceptibility to} 607948
COVID-19 research v1.38 TNF Sarah Leigh changed review comment from: TNF was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: TNF was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 10719836: Herbein et al. (Review) TNF is a proinflammatory cytokine plays a key role in the host response to viral infection. TNF enhances or inhibits viral replication depending on the virus involved and the cell type infected. The binding of TNF to the TNF receptors can activate, differentiate, or kill target cells thereby interfering with the viral life cycle. In contrast, viruses have evolved to appropriate the TNF/TNFR pathway to evade immune responses and favor viral dissemination. From OMIM: PMID: 12915457;Kim et al. (2003) To investigate whether TNF-alpha promoter polymorphisms are associated with clearance of hepatitis B virus (HBV) infection, Kim et al. (2003) genotyped 1,400 Korean subjects, 1,109 of whom were chronic HBV carriers and 291 who spontaneously recovered. The TNF promoter alleles that were previously reported to be associated with higher plasma levels (presence of -308A or the absence of -863A alleles), were strongly associated with the resolution of HBV infection. Haplotype analysis revealed that TNF-alpha haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and haplotype 2 (-1031C; -863A; -857C; -308G; -238G; -163G) were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively (P = 0.003-0.02). From OMIM: PMID: 11506397 Quasney et al. The presence of the A allele at the TNF-alpha-308 site was overrepresented among adults with HIV dementia compared to those without dementia (0.28 vs 0.07; OR 5.5; 95% CI 1.8-17.0) and a healthy control population (0.28 vs 0.11). The increased frequency of the A allele in HlV-infected adults with dementia suggests that this locus may play a role in the pathophysiology of dementia and suggests a genetic predisposition for the development of HIV dementia. PMID: 26657940 García-Ramírez et al. (2015) - 145 patients with influenza A (H1N1) (pA/H1N1), 133 patients with influenza-like illness (ILI), and 360 asymptomatic healthy contacts (AHCs) were included from a Mexican population were studied. The TNF-238 GA genotype was associated with an increased risk of disease severity (OR =16.06, p = 0.007). PMID: 31986264: Huang et al. (2020) Study of 41 patients admitted to hospital with laboratory-confirmed 2019-nCoV. Compared with non-ICU patients, ICU patients had higher plasma levels of proinflammatory cytokines and chemokines including IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
COVID-19 research v1.38 TNF Sarah Leigh Publications for gene: TNF were set to
COVID-19 research v1.37 NUP214 Sarah Leigh changed review comment from: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: PMID 31178128: Fichtman et al. (2019) reported four patients from two unrelated families with fever-induced, partially reversible acute encephalopathy and regression, progressive microcephaly, and brain atrophy. Febrile episodes were associated with viral infections. Exome sequencing identified that both affected individuals from family A were homozygous for the NUP214 NM_005085.3; c.112C>T (p.Arg38Cys) missense variant. A frameshift variant, c.1574delC (p.Pro525LeufsTer6) and a missense variant c.1159C>T (p.Pro387Ser), found in a compound heterozygous state were identified in the NUP214 gene in the two affected individuals from family B. The missense variants affected highly conserved residues and were present at a low frequency in gnomAD. Functional studies on primary skin fibroblasts derived from one case (family A1) supported pathogenicity of the p.Arg38Cys variant; NUP214 and NUP88 protein levels were reduced in while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays revealed defects in the classical protein import and mRNA export pathways in affected cells.
COVID-19 research v1.37 NUP214 Sarah Leigh Phenotypes for gene: NUP214 were changed from to {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426
COVID-19 research v1.36 NUP214 Sarah Leigh Publications for gene: NUP214 were set to
Congenital myopathy v2.5 CCDC78 Zornitza Stark reviewed gene: CCDC78: Rating: AMBER; Mode of pathogenicity: None; Publications: 22818856; Phenotypes: Myopathy, centronuclear, 4, 614807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v1.35 IL7 Sarah Leigh changed review comment from: IL7 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: IL7 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: PMID 25981006 – Horev et al. (2015) reported three cases from one consanguineous Arab family characterized by severe CD41T-cell lymphopenia, generalized verrucosis due to HPV infections, predisposition to opportunistic C. neoformans meningitis, and recurrent squamous cell carcinomas of the skin in sun-exposed areas. Whole exome sequencing analysis of one case (patient 3) identified a homozygous variant in the IL 7 gene, c.205A>T ( p.Arg69Ter). PMID: 31900472 Kosumi et al. (2020) reported two generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. IL-7 deficiency was not accompanied CD4 T lymphocytopenia, circulating CD4 T-cells were not depleted in one of the patients, suggesting a GV pathogenesis other than poor T-cell development.
COVID-19 research v1.35 IL7 Sarah Leigh Publications for gene: IL7 were set to 25981006
COVID-19 research v1.34 IL4R Sarah Leigh changed review comment from: IL4R was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IL4R was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: IL4R (interleukin 4 receptor), encodes the alpha chain of the interleukin-4 receptor [29], is a type I transmembrane protein that can bind both IL-4 (interleukin 4) and IL-13 (interleukin13) to regulate IgE production.
From OMIM: PMID: 16189667 Soriano et al. (2005)
By analysis of IL4R allele and genotype frequencies in individuals with different risk factors for human immunodeficiency virus (HIV) acquisition and different rates of progression to acquired immunodeficiency syndrome (AIDS), Soriano et al. (2005) determined that the V50 allele predominated in HIV-positive long-term nonprogressors (LTNPs), whereas the I50 allele predominated in healthy controls, typical progressors, and those at risk for infection due to sexual exposure or treatment of hemophilia. Homozygosity for V50 was increased in LTNPs compared with other groups. Soriano et al. (2005) concluded that V50 homozygosity appears to be associated with slow progression to AIDS after HIV infection.
PMID: 30228077: Useche et al.(2019)
A case-control study to evaluate possible associations between SNPs in IL4R and IL6R genes and clinical dengue in children from two Colombian populations, Huila and Antioquia. The study included 298 symptomatic children and 648 asymptomatic controls. The IL4R-rs1805016 GG genotype associated with clinical dengue in the pooled and Huila samples. No association of these polymorphisms in the sample of Antioquia.
PMID: 29287219: Yu et al. (2018)
Fifty-five chronic hepatitis B (CHB) patients, fifty-three self-healing HBV (SH) patients and 53 healthy controls (HC) were recruited, 404 cytokine and cytokine receptor related genes sequenced using NGS. The authors suggest that the IL4R SNPs; rs1805012 (p.Cys431Arg) and rs1805011 (p.Glu400Ala) are associated with chronic hepatitis B, there was no significant difference between the frequency of these variants between the CHB patients and the SH patients.
PMID: 31141539 Naget et al. EBV infection represses IL4R expression. Isolated EBV-positive and EBV-negative subclones from the DLBCL derived cell line DOHH-2 showed that EBV-encoded factors LMP1 and LMP2A activated the expression of HLX via STAT3. HLX in turn repressed NKX6-3, SPIB and IL4R which normally mediate plasma cell differentiation.
COVID-19 research v1.34 IL4R Sarah Leigh Phenotypes for gene: IL4R were changed from to {AIDS, slow progression to} 609423
COVID-19 research v1.33 IL4R Sarah Leigh Publications for gene: IL4R were set to
COVID-19 research v1.32 IL18BP Sarah Leigh changed review comment from: IL18BP was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: IL18BP was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: The IL18BP gene is located on chromosome 11 at 11q13.4 and encodes the interleukin 18 binding protein , a soluble inhibitor which mediates of the proinflammatory cytokine interleukin 18, an amplifier of natural killer (NK) cells, through a negative feedback loop (Harms et al. 2017). The IL18BP gene has been recently identified as candidate gene associated with a susceptibility to fulminant viral hepatitis (FVH), a form of acute liver failure that occurs in up to 0.5% of individuals following infection with liver-tropic viruses, most commonly hepatitis A or B. The proposed inheritance pattern is autosomal recessive with loss of function as a mechanism of disease. In 2019, Belkaya et al. describe an 11 year-old female child of Algerian ancestry who died of FVH following an acute hepatitis A infection. Through whole exome sequencing, she was found to be homozygous for an IL18BP deletion, c.508-19_528del. Her parents and one of her brothers were found to be heterozygous for the variant and a second brother did not carry the variant. Experiments using Epstein Barr virus-transformed B cells transfected with the c.508-19_528del variant and an in vitro bioassay suggest that the variant results in 3 abnormal novel transcripts which produce non-functional proteins with reduced expression. Additional experimental evidence described in the same publication include evaluation of liver tissue from the proband and a second individual with FVH, which showed elevated IL-18 staining compared to controls, functional experiments in a selection of human cell types which showed the upregulation of IL -18BP expression is in response to several inflammatory cytokines, and a cell culture model in which hepatitis A positive and negative hepatocytes were cultured with NK where stimulation with IL-18 resulted in hepatocyte death and treatment with IL-18BP resulted in a rescue. In summary, Belkaya et al. presents plausible clinical and experimental evidence suggesting that a susceptibility to FVH may be caused by a congenital absence or reduction of IL18BP. The gene disease association is currently limited as this is the first and only publication describing an association between IL18BP and FVH.
COVID-19 research v1.32 IL18BP Sarah Leigh Phenotypes for gene: IL18BP were changed from Defects in intrinsic and innate immunity; IL-18BP deficiency; inborn errors of immunity related to leukocytes to {?Hepatitis, fulminant viral, susceptibility to} 618549; Defects in intrinsic and innate immunity; IL-18BP deficiency; inborn errors of immunity related to leukocytes
COVID-19 research v1.31 IL18BP Sarah Leigh Publications for gene: IL18BP were set to 32086639; 32048120; 31213488; 32285199
COVID-19 research v1.30 IFNG Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients.
From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans.
PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups.
COVID-19 research v1.30 IFNG Sarah Leigh Publications for gene: IFNG were set to
COVID-19 research v1.29 IFITM3 Sarah Leigh changed review comment from: IFITM3 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IFITM3 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 20064371 Brass et al. (2009) used a functional genomic screen to identify IFITM3 as an antiviral restriction factor in influenza A H1N1 viral infection. Further characterization showed IFITM3 inhibits the early replication of flaviviruses, including dengue virus and West Nile virus. PMID: 27384652 Gorman et al. (2016) Ifitm3(-/-) mice are more vulnerable to lethal WNV infection than their wildtype littermates, this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. PMID: 22446628 Everitt et al. (2012). Ifitm3(-/-) mice display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, a phenotype which may be rescued by the re-introduction of Ifitm3. PMID: 22446628 Everitt et al. (2012). A statistically significant number of hospitalized with seasonal or pandemic influenza H1N1/09 viruses subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C). This SNP alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. PMID: 23361009 Zhang et al. (2013) In a Han Chinese patient population, the rs12252-C, CC genotype was found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. The CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. PMID: 25942469 Yang et al. (2015) performed meta-analysis of four studies consisting of 445 cases and 4180 controls. A significant association between a minor IFITM3 allele (SNP rs12252-C) with severe influenza susceptibility, but not in mild influenza subjects, in both UK Caucasians and Han Chinese population was confirmed. The rs12252-C allele causes a 23.7% higher chance of infection and also constitutes a risk factor for more severe influenza.
COVID-19 research v1.29 IFITM3 Sarah Leigh Publications for gene: IFITM3 were set to 32348495; 23361009
COVID-19 research v1.28 HLA-DRB1 Sarah Leigh Publications for gene: HLA-DRB1 were set to PMID: 19445991,26456283,19597844,10823757,
COVID-19 research v1.27 HLA-DQB1 Sarah Leigh changed review comment from: HLA-DQB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: HLA-DQB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: HLA-DQB1 alleles may have a role in influencing viral infection and pathogenesis: PMID:10609818: Thirsz et al. (1999) - The distribution of MHC class II alleles was compared between patients with self-limiting infection (n=85) and matched patients with persistent infection (n=170); between patients with mild (n=321) and severe (n=321) histological injury; and between patients who responded to interferon (n=96) and those who did not (n=192). The results of these comparisons were confirmed with a second-stage study of self-limiting infection (n=52) versus persistent infection (n=152). Self-limiting HCV infection was associated with HLA-DRB1*1101 (odds ratio 2.14 [95% CI 1.11-4.12]; p=0.013) and HLA-DQB1*0301 (2.22 [1.24-3.96], p=0.004). Persistent HCV infection was associated with HLA-DRB1*0701 (2.04 [1.03-4.17], p=0.027), and HLA-DRB4*0101 (2.38 [1.29-4.35], p=0.002). These results were confirmed in the second-stage study. No significant associations were found between MHC class II alleles and severe histological injury or response to interferon therapy. PMID:30563535 - Ou et al. (2019) - found that HLA-DQB1*06:03 protected against HBV infection. Levels of IFN-γ and IL-4 were significantly elevated in HBV cases with HLA-DQB1*06:05 (vs. HLA-DQB1*05:03), and the HBV group had higher DQB1 mRNA expression than the healthy control group with HLA-DQB1*05:03 and HLA-DQB1*06:02. The meta-analysis revealed that HLA-DQB1*04:01, HLA-DQB1*05:02, HLA-DQB1*05:03, and HLA-DQB1*06:01 were risk factors for HBV infection susceptibility, while HLA-DQB1*05:01, HLA-DQB1*06:03, and HLA-DQB1*06:04 protected against HBV infection. Spontaneous HBV clearance was associated withHLA-DQB1*06:04, while chronic HBV infection was associated with HLA-DQB1*02:01 and HLA-DQB105:02. DBQ1 typing can be used to identify patients who have elevated risks of HBV infection. PMID 31254396: Huang et al. (2019) - Recently reported a high prevalence and spontaneous clearance rate of HCV in a cohort of Chinese Li ethnicity who were infected with new variants of HCV genotype 6. In this study found that the distribution of HLA class I and class II alleles in HCV infected individuals of Chinese Li ethnicity (n = 143) was distinct from that of Chinese Han ethnicity. HLA-DRB1*11:01 and DQB1*03:01 were more prevalent in Chinese Li subjects who cleared HCV spontaneously than those who were chronically infected (P = .036 and P = .024, respectively), which were consistent with the previous report regarding the Chinese Han population. Multivariate logistic regression analysis showed that DQB1*03:01 (odds ratio = 3.899, P = .017), but not DRB1*11:01, associated with HCV spontaneous clearance, independent of age, sex, and IFNL3 genotype. Because DQB1*03:01 and DRB1*11:01 were tightly linked because of linkage disequilibrium, results clearly supported the associations of these two alleles with HCV spontaneous clearance in Chinese Li as well as Han ethnicity. PMID:23710940 - Chaaithanya et al. (2013) - study investigated the association of polymorphisms in the human leucocyte antigen class II genes with susceptibility or protection against CHIKV. Lower frequency of HLA-DQB1*03:03 was observed in CHIKV patients compared with the control population. Significantly lower frequency of glutamic acid at position 86 of peptide-binding pocket 1 coding HLA-DQB1 genotypes was observed in CHIKV patients compared with healthy controls. HLA-DQB1 alleles and critical amino acid differences in the peptide-binding pockets of HLA-DQB1 alleles might have role in influencing infection and pathogenesis of CHIKV.
COVID-19 research v1.27 HLA-DQB1 Sarah Leigh Publications for gene: HLA-DQB1 were set to
COVID-19 research v1.26 HLA-C Sarah Leigh changed review comment from: HLA-C was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: HLA-C was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: From OMIM: PMID: 11386265 - Gao et al. (2001) concluded that the previously observed association of HLA-Cw*04 with progression to AIDS was due to its linkage disequilibrium with HLA-B*35-Px alleles. PMID:17641165 - Fellay et al. (2007) identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these lies within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701 (142830.0003), whereas a second is located near the HLA-C gene. PMID:19933563 - Thomas et al. (2009) - Genotyped a previously identified varinat 35 kb upstream of the HLA-C gene in 1,698 patients of European ancestry with HIV. Tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. Found that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high surface expression better control viremia and progress more slowly to AIDS. Thomas et al. (2009) concluded that high HLA-C expression results in more effective control of HIV-1, possibly through better antigen presentation to cytotoxic T lymphocytes. PMID 21051598: International HIV Controllers Study performed a GWAS in a multiethnic cohort of HIV-1 controllers and progressors, and analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins and demonstrated HLA-C expression affects response to HIV - higher HLA-C expression is associated with better control of HIV-1.
COVID-19 research v1.26 HLA-C Sarah Leigh Phenotypes for gene: HLA-C were changed from to {HIV-1 viremia, susceptibility to} 609423
COVID-19 research v1.25 HLA-C Sarah Leigh Publications for gene: HLA-C were set to
COVID-19 research v1.24 FUT2 Sarah Leigh changed review comment from: FUT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: FUT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 30845670: Nordgren et al. (2019) (Review) The FUT2 gene encodes FUT2 enzyme, which catalyzes the transfer of fucose to the terminal galactose on glycan chains of cell surface glycoproteins and glycolipids, allowing the synthesis of histo-blood group antigens (HBGAs). The FUT2 gene is expressed predominately in epithelial (mucosal) tissues. Individuals with inactivated FUT2 enzyme, known as “non secretors” do not express blood group antigens in these tissues and are resistant to several norovirus genotypes. FUT2 polymorphisms with known effect on secretor status are present in different populations and are reviewed by Nordgren et al. (2019).
COVID-19 research v1.24 FUT2 Sarah Leigh Publications for gene: FUT2 were set to
COVID-19 research v1.23 DPP4 Sarah Leigh changed review comment from: DPP4 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA); to: DPP4 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA). "Illumina review: Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. DPP4 acts as a receptor for MERS-CoV - PMID: 24554656 - Barlan et al. (2014). MERS virus cell entry begins with the receptor-binding domains (RBDs) of the MERS-CoV protein virus spike (S) protein binding to blades 4 and 5 of the 8-blade propeller domain of DPP4. PMID:23486063 - Raj et al. (2013) - identified DPP4 as a functional receptor for hCoV-EMS (MERS CoV). Evidence from mouse models of involvment in susceptibility to MERS-CoV infection. PMID:24599590 - Zhao et al. (2014) - noted that rodents are not susceptible to MERS-CoV. They used an adenovirus vector expressing human DPP4 to generate mice sensitized to infection with MERS-CoV. These mice developed pneumonia characterized by extensive inflammatory cell infiltration with virus clearance after 6 to 8 days in a type I IFN- and T cell-dependent manner. Treatment with poly(I:C) was also efficacious in this model. PMID: 25589660 - Agrawal et al. (2015) developed a transgenic mouse model expressing human DPP4 that was susceptible to MERS-CoV infection, with high titers of virus detectable in brain and lung and later in other organs. PMID: 26124093 - Pascal et al. (2015) - obtained a mouse model susceptible to intranasal infection with MERS-CoV. Human monoclonal antibodies binding to the MERS-CoV S protein neutralized all variants of the virus and prevented entry into target cells. The antibodies could both prevent and treat mice humanized for DPP4. Pascal et al. (2015) concluded that the model will be valuable for assessing treatments for MERS-CoV infection and disease. PMID:31883094 - Leist et al. (2020) - generated a mouse model susceptible to MERS-CoV infection - used C57BL/6J mice and CRISPR/Cas9 to substitute human residues at positions 288 and 330 (A288L and T330R). Strollo et al. (2020) and Bassedine et al. (2020) suggested that DPP4 could affect severity of infection and also be a therapeutic target: PMID:32336077 - Strollo et al. (2020) - propose a role for DDP4 as a functional receptor for SARS-CoV-2 and ask the question if DPP4 is directly involved in SARS-CoV-2 cell adhesion/virulence, and whether DPP4 inhibition might be a therapeutic strategy for preventing infection. PMID:32394639 - Bassedine et al. (2020) - modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. Notes that increased DPP4 expression and activity are associated with diabetes, obesity, and metabolic syndrome, all of which have been reported to influence COVID‐19 severity. DPP4 inhibitors (gliptins), which vary in their interactions with the active site of the enzyme, may have immunomodulatory and cardioprotective effects that could be beneficial in COVID‐19 cases. PMID:31964246 - Keline-Weber at al. (2020) - Identified 14 polymorphisms in DPP4 from public databases that alter amino acid residus required for MERS-CoV S binding. Introduction of the respective variants into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.
COVID-19 research v1.23 TRIM69 Zornitza Stark gene: TRIM69 was added
gene: TRIM69 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: TRIM69 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TRIM69 were set to 22105173
Phenotypes for gene: TRIM69 were set to Susceptibility to herpes simplex encephalitis
Review for gene: TRIM69 was set to RED
Added comment: One individual with bi-allelic and one individual with mono-allelic variants in this gene described.
Sources: Expert list
COVID-19 research v1.23 DPP4 Sarah Leigh Added comment: Comment on phenotypes: This is not an official phenotype, just the observation from the literature
COVID-19 research v1.23 DPP4 Sarah Leigh Phenotypes for gene: DPP4 were changed from to Susceptiblity to MERS-CoV infection
COVID-19 research v1.22 DPP4 Sarah Leigh Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093; https://doi.org/10.1101/2020.04.30.071274; 31883094; 31964246
COVID-19 research v1.21 CX3CR1 Sarah Leigh changed review comment from: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: Receptor for the CX3C chemokine fractalkine (CX3CL1); binds to CX3CL1 and mediates both its adhesive and migratory functions. Acts as coreceptor with CD4 for HIV-1 virus envelope protein (in vitro) (PMID:9726990). Associated with rapid progression to AIDS from HIV1 infection. PMID:14607932: Garin et al. (2003) - identified two novel isoforms of the human chemokine receptor CX3CR1, produced by alternative splicing that appear to be more potent HIV coreceptors. PMID:10731151: Faure et al. (2000) - CX3CR1 is an HIV coreceptor as well as a leukocyte chemotactic/adhesion receptor for fractalkine. Faure et al. (2000) identified 2 single nucleotide polymorphisms in the CX3CR1 gene in Caucasians and demonstrated that HIV-infected patients homozygous for I249/M280 progressed to AIDS more rapidly than those with other haplotypes (relative risk = 2.13, P = 0.039). Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Concluded that CX3CR1-I249/M280 is a recessive genetic risk factor for HIV/AIDS. PMID 28228284: Zhivaki et al. (2017) - Upregulated in RSV infection affecting severity of infection. Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. Identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis. PMID unavailable: Strickland et al. (2020) - Pulmonary infection with C. neoformans (opportunistic fungal pathogen and leading cause of death in HIV-affected inividuals) enhanced CX3CR1 expression in the lung. Following infection, mice lacking CX3CR1 had significantly higher pulmonary fungal burdens, as well as decreased survival times compared to wild type mice. These infected CX3CR1 knockout mice also displayed higher expression of pro-inflammatory cytokines including MIP-2, MCP-1 and CCL7, but lower expression of anti-inflammatory cytokines such as IL-10. CX3CR1 deficiency resulted in mice having dramatically enhanced neutrophil accumulation in the lungs following infection.Depletion of neutrophils drastically improved lung CFU in infected knockout mice, indicating that excessive inflammation drove fungal growth. These data indicate that CX3CR1 expression is essential for host resistance to pulmonary cryptococcal infection by inhibiting excessive lung inflammation.
COVID-19 research v1.21 CX3CR1 Sarah Leigh Phenotypes for gene: CX3CR1 were changed from to {Rapid progression to AIDS from HIV1 infection} 609423
COVID-19 research v1.20 CX3CR1 Sarah Leigh Publications for gene: CX3CR1 were set to
COVID-19 research v1.19 CPT2 Sarah Leigh changed review comment from: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). "Illumina review: Evidence suggests that susceptibility to infection-induced acute encephalopathy-4 (IIAE4) is conferred by heterozygous or homozygous variation in the CPT2 gene on chromosome 1p32. PMID:20934285: Shinohara et al. (2011) - found 352C variant at a significantly higher frequency in 29 Japanese patients with IIAE compared to controls. Pathogens included influenza, adenovirus, HHV6. mycoplasma and rotovirus. No correlation between good and poor prognosis. PMID: 21697855: Mak et al. (2011) - Showed heterozygosity for the CPT2 F352C variant and homozygosity for the CPT2 V368I variant in two unrelated Chinese individuals with fatal virally-induced acute encephalopathy. PMID: 15811315: Chen et al. (2005) - thermolabile phenotype of compound heterozygotes for F352C and V368I which showed a higher frequency in Japanese influenza-associated encephalopathy patients than healthy volunteers. PMID 18306170: Yao et al. (2008) - large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homozygous/heterozygous variants in CPT2. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the wild type.
COVID-19 research v1.19 CPT2 Sarah Leigh Phenotypes for gene: CPT2 were changed from to {Encephalopathy, acute, infection-induced, 4, susceptibility to} 614212
COVID-19 research v1.18 CPT2 Sarah Leigh Publications for gene: CPT2 were set to
COVID-19 research v1.17 CLEC4M Sarah Leigh changed review comment from: CLEC4M was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA); to: CLEC4M was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA). Illumina review: CLEC4M is a C-type lectin gene serving as cell adhesion receptor and pathogen recognition receptor. It functions as a cellular receptor for variety of viruses, including HIV-1, hepatitis C, Ebola, and SARS-coronavirus. A highly polymorphic variable number tandem repeat (VNTR) at the neck-region of CLEC4M had been associated with genetic predisposition to some infectious diseases, however, genetic association studies have shown conflicting results about these associations (PMID:16991095;16369534;12738250;16364081;17321900;18697825;17534354;17534355). From OMIM: Associated with protection against SARs infection. PMID: 15496474: Jeffers et al. (2004) identified the cellular gylcoprotein CD209L (CLEC4M) as as an alternative receptor for SARS-CoV. CD209L is expressed in human lung in type II alveolar cells and endothelial cells, both potential targets for SARS-CoV. Several other enveloped viruses, including Ebola and Sindbis, also use CD209L as a portal of entry, and HIV and hepatitis C virus can bind to CD209L on cell membranes but do not use it to mediate virus entry. Jeffers et al. (2004) suggested that the large S glycoprotein of SARS-CoV may use both ACE2 and CD209L in virus infection and pathogenesis. PMID 16369534: Chan et al. (2006) - demonstrated that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. CLEC4M was expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for CLEC4M, cells homozygous for CLEC4M showed higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation, and a lower capacity for trans infection. Thus, homozygosity for CLEC4M plays a protective role during SARS infection. PMID: 17534354: Tang et al. (2007) - performed genotyping studies in SARS patients and controls and found no support for an association between homozygosity for CLEC4M and protection against SARS. PMID:17534355: Zhi et al. (2007) also failed to replicate the study by Chan et al. (2006). Chan et al. (2007) disputed the validity of both studies. PMID 18697825:Li et al. (2008) - genotyped SNPs in CLEC4M and other genes in the C-type lectin cluster in 181 Chinese SARS patients and 172 controls from an ethnically matched population and found no significant association with disease predisposition or prognosis. However, they detected a population stratification of the CLEC4M variable number tandem repeat (VNTR) alleles in a sample of 1,145 Han Chinese from different parts of China (northeast, south, and southwest). Analysis extended to 742 individuals from 7 ethnic minorities showed that those located along the Silk Road in northwestern China, where there is significant admixture with the European gene pool, had a low level of homozygosity, similar to European populations. Li et al. (2008) concluded that there is no SARS predisposition allele in the lectin gene cluster at chromosome 19p13.3, and that the previously reported association with polymorphisms in the CLEC4M neck region may be due to population stratification.
COVID-19 research v1.17 CLEC4M Sarah Leigh Publications for gene: CLEC4M were set to
COVID-19 research v1.16 CIB1 Sarah Leigh changed review comment from: CIB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: CIB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). "Illumina review: From OMIM: Susceptibility to epidermodysplasia verruciformis-3 is conferred by homozygous variation in the CIB1 gene. Epidermodysplasia verruciformis-3 is characterized by onset in childhood or early adulthood of persistent disseminated flat warts and pityriasis versicolor-like lesions of the skin that are induced by cutaneous human papillomaviruses (HPVs) of the beta genus. Some patients develop nonmelanoma skin cancer, particularly on areas of the body exposed to the sun. Patients are otherwise healthy and normally resistant to other microorganisms, including other viruses and skintropic pathogens, and even all other cutaneous and mucosal HPVs. Gene:disease relationship with autosomal recessive epidermodysplasia verruciformis curated using the ClinGen framework for gene curation. The CIB1 gene is located on chromosome 15 at 15q26.1 and encodes calcium and integrin binding 1. This protein forms a complex with the products of the TMC6 (EVER1) and TMC8 (EVER2) genes. The CIB1/EVER1/EVER2 complex acts to restrict transcription of human papillomaviruses. The CIB1 gene was first reported in relation to autosomal recessive epidermodysplasia verruciformis in 2018 (PMID: 300068544). Five unique homozygous variants in this gene were reported in at least five probands including two frameshift, one stop-gained, one stop-lost, and one canonical splice variant. The evidence supporting the GDR includes segregation data - linkage analysis across three unrelated families of differing geographic origin resulted in a LOD score of 16.7. This gene-disease relationship is also supported by expression data and a shared biochemical function with additional genes that are also associated with the disease (PMID: 300068544). In summary, the GDR between CIB1 and autosomal recessive epidermodysplasia verruciformis is classified as strong using the ClinGen framework.
COVID-19 research v1.16 CIB1 Sarah Leigh Publications for gene: CIB1 were set to 32086639; 32048120
COVID-19 research v1.15 CD209 Sarah Leigh changed review comment from: CD209 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CD209 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: One SNP associated with susceptibility to HIV infection, severity of dengue disease, increased risk of TB and severity of SARS infection. Pathogen-recognition receptor expressed on the surface of immature dendritic cells (DCs) and involved in initiation of primary immune response. Thought to mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. The receptor returns to the cell membrane surface and the pathogen-derived antigens are presented to resting T-cells via MHC class II proteins to initiate the adaptive immune response. From OMIM:The C-type lectin receptors are involved in the primary interface between host and pathogens. PMID:15564514: Martin et al. (2004) - European Americans at risk for parenteral HIV infection were more likely to carry the -336C SNP in the promoter of DCSIGN. This association was not observed in those at risk for mucosally acquired infection. Although the -336C SNP was common in African Americans, no significant association with risk of infection was observed in this group. PMID:15838506: Sakuntabhai et al. (2005) found that the same CD209 promoter polymorphism reported by Martin et al. (2004) (-336A>G in this study), was associated with severity of dengue disease. Specifically, the G allele of the variant was associated with strong protection against dengue fever as opposed to dengue hemorrhagic fever. PMID:16379498:Barreiro et al. (2006) looked at CD209 polymorphisms in 351 TB patients and 360 healthy controls from a South African Coloured population living in communities with some of the highest reported incidence rates of TB in the world. Identified two variants in the CD209 promoter, -871A and -336G, that were associated with increased risk of TB. PMID:20864747: Chan et al. (2010) - A single nucleotide polymorphism in the promoter region of the DC-SIGN gene is associated with disease severity in SARS. In the DC_SIGN promoter region, a single SNP, -336A>G has been found to affect transcription of DC-SIGN in vitro and is associated with susceptibility for HIV-1 and M. tuberculosis infectsions and with the severity of dengue (PMID:15838506;15838506;16379498). Large case-control study - genotyped the SNP in 824 SARS patients and 471 controls. Showed no association with susceptibility to infection but SARS patients carrying the DC-SIGN promoter -336G variant had lower risk of having higher lactate dehydrogenase levels on admission, an independent prognostic indicator for severity of SARS-CoV infection. In vitro functional studies demonstrated that the DC-SIGN -336G promoter provided a less effective binding site and lower promoter activity, which may lead to reduced DC-SIGN protein expression and hence may contribute to a reduced immune-response with reduced lung injury during the progression of SARS infection.
COVID-19 research v1.15 CD209 Sarah Leigh Publications for gene: CD209 were set to
COVID-19 research v1.14 CCR5 Sarah Leigh changed review comment from: CCR5 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CCR5 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: Cytokine receptor. From OMIM: Variation in the CCR5 gene is associated with susceptibility to West Nile Virus (PMID 16230476;21935451;19247438). Numerous studies additionally demonstrate variation in CCR5 is associated with resistance / susceptibility to HIV and HBV infection. PMID 24098976: Zapata et al. (2013) - main genetic factor related to HIV-1 resistance is the CCR5-Δ32 variant. The CCR5-Δ32 variant along with SNPs in the CCR5 promoter and the CCR2-V64I variant have been included in seven human haplogroups (HH) previously associated with resistance/susceptibility to HIV-1 infection and different rates of AIDS progression. This study determined the association of the CCR5 promoter SNPs, the CCR5-Δ32 mutation, CCR2-V64I SNP, and HH frequencies with resistance/susceptibility to HIV-1 infection in a cohort of HIV-1-serodiscordant couples from Colombia. The CCR5-Δ32 allele is not responsible for HIV-1 resistance in this HESN group; however, the CCR2-I allele could be protective, while the 29G allele might increase the likelihood of acquiring HIV-1 infection. HHG1 and the AGACCAC-CCR2-I-CCR5 wild-type haplotype might promote HIV-1 infection while HHF2 might be related to resistance. PMID 31686727: Moudi et al. (2019) - study evaluated the association between the CCR5-Δ32, CCR5-2459A/G, MCP-1-2518A/G, VDR-APa1A/C, VDR-Taq1T/C SNPs and HBV susceptibility, in samples of Iranian populations. Significant associations with susceptibility to chronic HBV infection was observed with CCR5-2459A/G, MCP1-2518A/G, VDR-APa1A/C, VDR-Taq1T/C polymorphisms. In addition, no association of the CCR5D32 SNP with the disease was found. PMID:31100442 - Koor et al. (2019) - 9 CCR5 haplotypes are defined by seven 5'UTR SNPs in HIV-1 disease. Study identified key SNPs in HIV-1 control in both controllers and progressors.
COVID-19 research v1.14 CCR5 Sarah Leigh Publications for gene: CCR5 were set to 16230476; 21935451; 19247438; 24098976; 31686727; 31100442; https://doi.org/10.1101/2020.05.02.20084673
COVID-19 research v1.13 CCR5 Sarah Leigh Publications for gene: CCR5 were set to
COVID-19 research v1.12 CCL11 Sarah Leigh changed review comment from: CCL11 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CCL11 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: CCL11 is a cytokine released in response to viral infections. No evidence found of SNPs in association with SARS-CoV-2 infection. From OMIM: PMID: 14571188: Modi et al. (2003) identified 3 SNPs that formed a 31-kb haplotype (H7) spanning the CCL2-CCL7-CCL11 gene cluster on chromosome 17q. The SNPs and the H7 haplotype were significantly associated with protection from HIV-1 infection. PMID:30915442: Hoffman et al. (2019) - West Nile virus infection outcome vary among individuals with most infections resulting in asymptomatic or mild-flu like symptoms. WNV-infected females reported more symptoms than males. Males were shown to exibit a protracted cytokine response including CCL11 (and CCL2, CXCL10 and IL-15) that was absent in females. PMID:32416070: Blanco-Melo et al. (2020) - look at the transcriptional response to SARS-CoV-2 compared to other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. SARS-CoV-2 shown to induce robust levels of chemokines including CCL2, CCl8 and CCL11 (Figure 4A).
COVID-19 research v1.12 CCL11 Sarah Leigh Publications for gene: CCL11 were set to 14571188; 30915442
COVID-19 research v1.11 TNF Alison Coffey reviewed gene: TNF: Rating: GREEN; Mode of pathogenicity: ; Publications: 10719836, 12915457, 11506397, 26657940, 31986264; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 NUP214 Alison Coffey reviewed gene: NUP214: Rating: RED; Mode of pathogenicity: ; Publications: 31178128; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 IL7 Alison Coffey reviewed gene: IL7: Rating: AMBER; Mode of pathogenicity: ; Publications: 31900472, 25981006; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 IL4R Alison Coffey reviewed gene: IL4R: Rating: RED; Mode of pathogenicity: ; Publications: 16189667, 30228077, 29287219, 31141539; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 IL18BP Alison Coffey reviewed gene: IL18BP: Rating: AMBER; Mode of pathogenicity: ; Publications: 31213488, 28900426; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 IFNG Alison Coffey reviewed gene: IFNG: Rating: GREEN; Mode of pathogenicity: ; Publications: 178981204, 17215375, 12854077, 26458193; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 IFITM3 Alison Coffey reviewed gene: IFITM3: Rating: GREEN; Mode of pathogenicity: ; Publications: 20064371, 27384652, 22446628, 23361009, 25942469; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 HLA-DRB1 Alison Coffey reviewed gene: HLA-DRB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19445991, 26456283, 19597844, 10823757, 29315655, 27512511; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 HLA-DQB1 Alison Coffey reviewed gene: HLA-DQB1: Rating: RED; Mode of pathogenicity: ; Publications: 10609818, 30563535, 31254396, 23710940; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 HLA-C Alison Coffey reviewed gene: HLA-C: Rating: RED; Mode of pathogenicity: ; Publications: 11386265, 17641165, 19933563; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 FUT2 Alison Coffey reviewed gene: FUT2: Rating: GREEN; Mode of pathogenicity: ; Publications: 30845670; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 DPP4 Alison Coffey reviewed gene: DPP4: Rating: AMBER; Mode of pathogenicity: ; Publications: 24554656, 23486063, 24599590, 25589660, 26124093, 31883094, 32336077, 32394639, 31964246; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CX3CR1 Alison Coffey reviewed gene: CX3CR1: Rating: AMBER; Mode of pathogenicity: ; Publications: 9726990, 14607932, 10731151, 28228284; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CPT2 Alison Coffey reviewed gene: CPT2: Rating: AMBER; Mode of pathogenicity: ; Publications: 20934285, 21697855, 15811315, 18306170; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CLEC4M Alison Coffey reviewed gene: CLEC4M: Rating: RED; Mode of pathogenicity: ; Publications: 16991095, 16369534, 12738250, 16364081, 17321900, 18697825, 17534354, 17534355, 15496474, 16369534, 17534354, 18697825; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CIB1 Alison Coffey reviewed gene: CIB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 300068544; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CD209 Alison Coffey reviewed gene: CD209: Rating: AMBER; Mode of pathogenicity: ; Publications: 15564514, 15838506, 16379498, 20864747; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CCR5 Alison Coffey reviewed gene: CCR5: Rating: AMBER; Mode of pathogenicity: ; Publications: 16230476, 21935451, 19247438, 24098976, 31686727, 31100442 ; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.11 CCL11 Alison Coffey reviewed gene: CCL11: Rating: AMBER; Mode of pathogenicity: ; Publications: 14571188, 30915442, 32416070; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.10 TNF Sarah Leigh commented on gene: TNF: TNF was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 NUP214 Sarah Leigh commented on gene: NUP214: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility)
COVID-19 research v1.10 IL7 Sarah Leigh commented on gene: IL7
COVID-19 research v1.10 IL4R Sarah Leigh commented on gene: IL4R: IL4R was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 IL18BP Sarah Leigh commented on gene: IL18BP
COVID-19 research v1.10 IFNG Sarah Leigh commented on gene: IFNG: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 IFITM3 Sarah Leigh commented on gene: IFITM3: IFITM3 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 HLA-DRB1 Sarah Leigh commented on gene: HLA-DRB1
COVID-19 research v1.10 HLA-DQB1 Sarah Leigh commented on gene: HLA-DQB1: HLA-DQB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 HLA-C Sarah Leigh commented on gene: HLA-C: HLA-C was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 GC Sarah Leigh commented on gene: GC
COVID-19 research v1.10 FUT2 Sarah Leigh commented on gene: FUT2
COVID-19 research v1.10 DPP4 Sarah Leigh commented on gene: DPP4: DPP4 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA)
COVID-19 research v1.10 CX3CR1 Sarah Leigh commented on gene: CX3CR1: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 CPT2 Sarah Leigh commented on gene: CPT2: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility)
COVID-19 research v1.10 CLEC4M Sarah Leigh commented on gene: CLEC4M
COVID-19 research v1.10 CIB1 Sarah Leigh commented on gene: CIB1: CIB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility)
COVID-19 research v1.10 CD209 Sarah Leigh commented on gene: CD209: CD209 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 CCR5 Sarah Leigh commented on gene: CCR5: CCR5 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 CCL11 Sarah Leigh commented on gene: CCL11: CCL11 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility)
COVID-19 research v1.10 ACE2 Sarah Leigh commented on gene: ACE2: ACE2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA)
COVID-19 research v1.9 GC Alison Coffey reviewed gene: GC: Rating: RED; Mode of pathogenicity: ; Publications: 2883392, 2895851; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v1.9 ACE2 Alison Coffey reviewed gene: ACE2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32228252; Phenotypes: ; Mode of inheritance: Unknown
Congenital myopathy v2.5 ECEL1 Zornitza Stark reviewed gene: ECEL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.5 ADSSL1 Zornitza Stark changed review comment from: Onset is specifically in adolescence so not appropriate for congenital panel.; to: Onset is in late childhood/adolescence so not appropriate for congenital panel.
Congenital myopathy v2.5 ADSSL1 Zornitza Stark edited their review of gene: ADSSL1: Changed publications: 26506222, 32331917
Congenital myopathy v2.5 ADSSL1 Zornitza Stark reviewed gene: ADSSL1: Rating: RED; Mode of pathogenicity: None; Publications: 26506222; Phenotypes: Myopathy, distal, 5, MIM# 617030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.5 ACTN2 Zornitza Stark reviewed gene: ACTN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30701273, 30900782; Phenotypes: Myopathy, congenital with structured cores and Z-line abnormalities 618654, Myopathy, distal, 6, adult onset 618655; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.5 GFER Zornitza Stark reviewed gene: GFER: Rating: GREEN; Mode of pathogenicity: None; Publications: 28155230; Phenotypes: Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, MIM#613076; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
COVID-19 research v1.8 IL6 Louise Daugherty Deleted their review
COVID-19 research v1.8 IRF4 Louise Daugherty Deleted their review
COVID-19 research v1.8 IRF4 Louise Daugherty commented on gene: IRF4
COVID-19 research v1.8 IL6 Louise Daugherty commented on gene: IL6
Intellectual disability v3.89 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Amber List (moderate evidence)
Intellectual disability v3.89 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.88 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo. However, only two of these cases did not have additional genetic changes reported.
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo, however, one of these cases also had a 290Kb deletion at
13q12.11.
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.92 CDC42BPB Sarah Leigh Added comment: Comment on mode of inheritance: Unknown mode of inheritance has been assigned as the majority of variants in this gene (11/14) in PMID 32031333 are de novo.
Early onset or syndromic epilepsy v2.92 CDC42BPB Sarah Leigh Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Intellectual disability v3.88 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Green List (high evidence)
Intellectual disability v3.88 CDC42BPB Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. intellectual disability was apparent in 7/12 cases and at least 5 of these cases were de novo.
Intellectual disability v3.88 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo.
Differences in sex development v2.4 PBX1 Zornitza Stark gene: PBX1 was added
gene: PBX1 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: PBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PBX1 were set to 31302614; 31058389
Phenotypes for gene: PBX1 were set to 46, XY gonadal dysgenesis
Review for gene: PBX1 was set to AMBER
Added comment: Two individuals reported with mono allelic variants in this gene and 46,XY gonadal dysgenesis.
Sources: Literature
Intellectual disability v3.87 DSCR3 Zornitza Stark gene: DSCR3 was added
gene: DSCR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DSCR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSCR3 were set to 31845315
Phenotypes for gene: DSCR3 were set to Intellectual disability, no OMIM # yet
Review for gene: DSCR3 was set to RED
Added comment: 1 family/2 cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Both shared the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals.
Sources: Literature
Ectodermal dysplasia v1.6 LEF1 Zornitza Stark gene: LEF1 was added
gene: LEF1 was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: LEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LEF1 were set to 32022899
Phenotypes for gene: LEF1 were set to Ectodermal dysplasia, no OMIM# yet
Review for gene: LEF1 was set to RED
Added comment: In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. One report of two unrelated patients with 4q25 de novo deletion encompassing LEF1 , associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. No reports of SNVs.
Sources: Literature
Skeletal dysplasia v2.9 ANO5 Zornitza Stark reviewed gene: ANO5: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32112655; Phenotypes: Gnathodiaphyseal dysplasia, MIM# 166260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Green List (high evidence)
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and of these cases were de novo.
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Green List (High Evidence).
Intellectual disability v3.87 CDC42BPB Sarah Leigh Added comment: Comment on phenotypes: CDC42BPB-related Neurodevelopmental Disorder is assigned by Gen2Phen.
Intellectual disability v3.87 CDC42BPB Sarah Leigh Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Early onset or syndromic epilepsy v2.90 CDC42BPB Sarah Leigh Added comment: Comment on phenotypes: CDC42BPB-related Neurodevelopmental Disorder is assigned by Gen2Phen.
Early onset or syndromic epilepsy v2.90 CDC42BPB Sarah Leigh Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Intellectual disability v3.86 NFASC Sarah Leigh Publications for gene: NFASC were set to 28940097; 30124836; 30850329
Likely inborn error of metabolism v2.12 DDC Sarah Leigh Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency to Aromatic L-amino acid decarboxylase deficiency 608643
Likely inborn error of metabolism v2.11 DDC Sarah Leigh Publications for gene: DDC were set to 27604308; 24816252
Intellectual disability v3.85 TMX2 Sarah Leigh Publications for gene: TMX2 were set to 31586943; 31270415
Arrhythmogenic right ventricular cardiomyopathy v2.6 FLNC Sarah Leigh Added comment: Comment on publications: PMID 31924696 reports two new trucating variants in cases of arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy v2.6 FLNC Sarah Leigh Publications for gene: FLNC were set to 27908349; 26666891
Ocular coloboma v1.36 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Ocular coloboma v1.36 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Ocular coloboma v1.36 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.7 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Structural eye disease v1.7 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Structural eye disease v1.7 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.25 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Anophthalmia or microphthalmia v1.25 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Anophthalmia or microphthalmia v1.25 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.9 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Skeletal dysplasia v2.9 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Skeletal dysplasia v2.9 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Chondrodysplasia punctata v1.4 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Chondrodysplasia punctata v1.4 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Chondrodysplasia punctata v1.4 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.84 C16orf62 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).; to: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).
Ocular coloboma v1.35 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Ocular coloboma. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Structural eye disease v1.6 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Structural eye disease. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Anophthalmia or microphthalmia v1.24 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Anophthalmia or microphthalmia. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Skeletal dysplasia v2.8 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Skeletal dysplasia. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Chondrodysplasia punctata v1.3 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Chondrodysplasia punctata. Sources: Literature
new-gene-name tags were added to gene: C16orf62.
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 31712251
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature
Intellectual disability v3.84 C16orf62 Sarah Leigh Publications for gene: C16orf62 were set to 25434475
CAKUT v1.152 DACT1 Eleanor Williams changed review comment from: Conference presentation/abstract - C14.2 - Heterozygous DACT1 mutations in patients with renal anomalies and features of Townes-Brocks syndrome Helge Martens - WES in a patient with renal anomalies, i.e. left-sided agenesis and right-sided duplex, who also had extrarenal abnormalities, e.g. anorectal and sacral malformation, They found a rare heterozygous missense variant in DACT1 gene. The variant was inherited from an unaffected mother. Then looked in further patients and found 7 maternally inherited, heterozygous, likely pathogenic DACT1 missense variants in 8 of 209 families. Appears to be reduced penetrance. Functional assays found Dact1 expression in different organs including anal canal and kidney, whereby renal expression was confined to the mesenchyme of ureter, kidney capsule, cortical and medullary stroma in mouse embryos. CRISPR/Cas9-derived Dact1-deficient murine inner medullary collecting duct cells showed impaired tubule formation. No publication relating to this data is found in PubMed.; to: ESHG 2020 Conference presentation/abstract - C14.2 - Heterozygous DACT1 mutations in patients with renal anomalies and features of Townes-Brocks syndrome Helge Martens - WES in a patient with renal anomalies, i.e. left-sided agenesis and right-sided duplex, who also had extrarenal abnormalities, e.g. anorectal and sacral malformation, They found a rare heterozygous missense variant in DACT1 gene. The variant was inherited from an unaffected mother. Then looked in further patients and found 7 maternally inherited, heterozygous, likely pathogenic DACT1 missense variants in 8 of 209 families. Appears to be reduced penetrance. Functional assays found Dact1 expression in different organs including anal canal and kidney, whereby renal expression was confined to the mesenchyme of ureter, kidney capsule, cortical and medullary stroma in mouse embryos. CRISPR/Cas9-derived Dact1-deficient murine inner medullary collecting duct cells showed impaired tubule formation. No publication relating to this data is found in PubMed.
CAKUT v1.152 DACT1 Eleanor Williams commented on gene: DACT1
CAKUT v1.152 FOXD2 Eleanor Williams gene: FOXD2 was added
gene: FOXD2 was added to CAKUT. Sources: Other
Mode of inheritance for gene: FOXD2 was set to BIALLELIC, autosomal or pseudoautosomal
Added comment: Conference presentation/abstract ESGH 2020 - Implication of FOXD2 in autosomal recessive syndromic CAKUT Korbinian M. Riedhammer Report index patient with CAKUT with a homozygous frameshift variant in FOXD2 NM_004474.3:c.789dup, p.(Gly264Argfs*228). The patient presented with bilateral hypoplastic kidneys, facial dysmorphism, developmental delay. Another affected family member was found to have the same variant. FOXD2 is a transcription factor with strong expression in the developing kidney. Foxd2-/- mice can show a CAKUT phenotype. No publications in PubMed relating to this data are currently found.
Sources: Other
Intellectual disability v3.83 SRCAP Eleanor Williams commented on gene: SRCAP
Intellectual disability v3.83 SATB1 Eleanor Williams changed review comment from: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other; to: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report 26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other
Intellectual disability v3.83 SATB1 Eleanor Williams gene: SATB1 was added
gene: SATB1 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SATB1 were set to intellectual disability
Review for gene: SATB1 was set to AMBER
Added comment: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants.
No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now.
Sources: Other
Holoprosencephaly - NOT chromosomal v2.5 STAG2 Shane Mckee gene: STAG2 was added
gene: STAG2 was added to Holoprosencephaly. Sources: Other
Mode of inheritance for gene: STAG2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: STAG2 were set to PMID: 31334757
Phenotypes for gene: STAG2 were set to holoprosencephaly
Penetrance for gene: STAG2 were set to Incomplete
Review for gene: STAG2 was set to GREEN
Added comment: Loss of function mutations in females leading to holoprosencephaly and linked midline brain disorders as per Kruszka et al
Sources: Other
Holoprosencephaly - NOT chromosomal v2.5 SMC1A Shane Mckee gene: SMC1A was added
gene: SMC1A was added to Holoprosencephaly. Sources: Other
Mode of inheritance for gene: SMC1A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: SMC1A were set to PMID: 31334757
Phenotypes for gene: SMC1A were set to holoprosencephaly; single central incisor
Penetrance for gene: SMC1A were set to Incomplete
Review for gene: SMC1A was set to GREEN
Added comment: Cohesin complex genes SMC1A, STAG4 etc need added to the panel; loss of function mutations in females (X-linked dominant)
Sources: Other
Cystic kidney disease v2.17 COL4A4 John Sayer gene: COL4A4 was added
gene: COL4A4 was added to Cystic kidney disease. Sources: Other
Mode of inheritance for gene: COL4A4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COL4A4 were set to 31922066
Phenotypes for gene: COL4A4 were set to cystic kidney disease
Penetrance for gene: COL4A4 were set to unknown
Review for gene: COL4A4 was set to AMBER
Added comment: may phenocopy PKD1
Sources: Other
Cystic kidney disease v2.17 COL4A5 John Sayer changed review comment from: COLA5 may cause mild cystic kidney disease
Sources: Other; to: COL4A5 may cause mild cystic kidney disease
Sources: Other
Cystic kidney disease v2.17 COL4A5 John Sayer gene: COL4A5 was added
gene: COL4A5 was added to Cystic kidney disease. Sources: Other
Mode of inheritance for gene: COL4A5 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: COL4A5 were set to 31922066
Phenotypes for gene: COL4A5 were set to cystic kidney disease
Penetrance for gene: COL4A5 were set to unknown
Review for gene: COL4A5 was set to GREEN
Added comment: COLA5 may cause mild cystic kidney disease
Sources: Other
Congenital myopathy v2.5 KY Zornitza Stark reviewed gene: KY: Rating: GREEN; Mode of pathogenicity: None; Publications: 11136708, 27485408, 27484770, 30591934; Phenotypes: Myopathy, myofibrillar, 7, MIM#617114; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.82 C16orf62 Sarah Leigh Classified gene: C16orf62 as Amber List (moderate evidence)
Intellectual disability v3.82 C16orf62 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Intellectual disability v3.82 C16orf62 Sarah Leigh Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.81 C16orf62 Sarah Leigh commented on gene: C16orf62: The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Intellectual disability v3.81 C16orf62 Sarah Leigh Tag new-gene-name tag was added to gene: C16orf62.
Intellectual disability v3.81 C16orf62 Sarah Leigh gene: C16orf62 was added
gene: C16orf62 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 25434475
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: Sources: Literature
Limb disorders v2.5 SMO Zornitza Stark reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 32413283; Phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
CAKUT v1.151 BMP4 Rebecca Foulger changed review comment from: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: evidence is borderline and. further cases or supportive evidence is needed to be confident of a causal link. Rated Amber but can be re-assessed by GLH groups at a future date.; to: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: evidence is borderline and further cases or supportive evidence is needed to be confident of a causal link. Rated Amber but can be re-assessed by GLH groups at a future date.
COVID-19 research v1.8 TRBC1 Sarah Leigh Classified gene: TRBC1 as Red List (low evidence)
COVID-19 research v1.8 TRBC1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Inactivating TRB locus SNPs and deletions polymorphisms in most human ethnic groups may result in virus-specific T-cell receptor diversity (PMID 22323539). TRBC1 T-cell responses may have a place in immunotherapeutic strategies for HIV infection (PMID 30932962).
COVID-19 research v1.8 TRBC1 Sarah Leigh Gene: trbc1 has been classified as Red List (Low Evidence).
COVID-19 research v1.7 TRBC1 Sarah Leigh Publications for gene: TRBC1 were set to 22323539
COVID-19 research v1.6 KIR2DL2 Rebecca Foulger Classified gene: KIR2DL2 as Red List (low evidence)
COVID-19 research v1.6 KIR2DL2 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red as not currently reportable- KIR2DL2 is on a non-standard (patch) chromosome.
COVID-19 research v1.6 KIR2DL2 Rebecca Foulger Gene: kir2dl2 has been classified as Red List (Low Evidence).
Intellectual disability v3.80 RBL2 Zornitza Stark gene: RBL2 was added
gene: RBL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RBL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBL2 were set to 32105419; 9806916
Phenotypes for gene: RBL2 were set to intellectual diability
Review for gene: RBL2 was set to RED
Added comment: Single family reported with pair of affected siblings. Supportive mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.89 GRM7 Zornitza Stark gene: GRM7 was added
gene: GRM7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 32286009; 32248644
Phenotypes for gene: GRM7 were set to Epilepsy, microcephaly, developmental delay
Review for gene: GRM7 was set to GREEN
gene: GRM7 was marked as current diagnostic
Added comment: Eleven individuals from six families reported, three different homozygous variants (two missense, one LoF). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Supportive mouse model.
Sources: Literature
Glycogen storage disease v1.3 PYGM Zornitza Stark reviewed gene: PYGM: Rating: GREEN; Mode of pathogenicity: None; Publications: 32386344; Phenotypes: McArdle disease, MIM# 232600, Glycogen storage disease, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v1.5 KIR2DL2 Rebecca Foulger commented on gene: KIR2DL2
COVID-19 research v1.5 KIR2DL2 Alison Coffey reviewed gene: KIR2DL2: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: 22022261, 22216211, 31288555; Phenotypes: ; Mode of inheritance:
Ichthyosis and erythrokeratoderma v1.3 PERP Zornitza Stark gene: PERP was added
gene: PERP was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: PERP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PERP were set to 31898316
Phenotypes for gene: PERP were set to Erythrokeratoderma, no OMIM # yet
Review for gene: PERP was set to AMBER
Added comment: One extended multiplex consanguineous family with Erythrokeratoderma (striking similarity to that observed in Perp −/− mice), and a novel homozygous variant (c.466G>A; p.Gly156Arg) in PERP that fully segregated with the phenotype. Functional analysis of patient‐ and control‐derived keratinocytes revealed a deleterious effect of the identified variant on the intracellular localization of PERP. A previous report showed that PERP mutation causes a dominant form of keratoderma but a single patient in that report with a homozygous variant in PERP suggests that recessive inheritance is also possible.
Sources: Literature
Differences in sex development v2.4 NR2F2 Zornitza Stark edited their review of gene: NR2F2: Set current diagnostic: yes
Differences in sex development v2.4 NR2F2 Zornitza Stark gene: NR2F2 was added
gene: NR2F2 was added to Disorders of sex development. Sources: Expert list
Mode of inheritance for gene: NR2F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR2F2 were set to 29478779; 31687637
Phenotypes for gene: NR2F2 were set to 46,XX disorder of sex development (DSD) and congenital heart defects
Review for gene: NR2F2 was set to GREEN
Added comment: Four unrelated individuals reported. Note two had the same 7bp deletion, c.97_103delCCGCCCG, NM_021005.3, and the third individual had an adjacent deletion, c.103_109delGGCGCCC, NM_021005.3. All three were of very different ancestries, making founder effect unlikely. Fourth individual had a larger deletion encompassing this gene. Gene is also linked with isolated CHD (Congenital heart defects, multiple types, 4, MIM# 615779)
Sources: Expert list
Arthrogryposis v3.11 ADCY6 Zornitza Stark reviewed gene: ADCY6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24319099, 26257172, 31846058; Phenotypes: Lethal congenital contracture syndrome 8, OMIM # 616287; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
COVID-19 research v1.4 TRBC1 Sarah Leigh Publications for gene: TRBC1 were set to
Intellectual disability v3.80 OTUD7A Zornitza Stark gene: OTUD7A was added
gene: OTUD7A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, intellectual disability, no OMIM# yet
Review for gene: OTUD7A was set to RED
Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.
Sources: Literature
Choanal atresia v1.13 KMT2D Zornitza Stark gene: KMT2D was added
gene: KMT2D was added to Choanal atresia. Sources: Literature
Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2D were set to 31949313
Phenotypes for gene: KMT2D were set to KMT2D-associated neurodevelopmental syndrome
Review for gene: KMT2D was set to GREEN
gene: KMT2D was marked as current diagnostic
Added comment: The association between LoF variants in KMT2D and Kabuki syndrome is well established. Note new association between missense variants located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism. 7 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability.
Sources: Literature
Intellectual disability v3.80 COG4 Zornitza Stark edited their review of gene: COG4: Set current diagnostic: yes
Intellectual disability v3.80 COG4 Zornitza Stark reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31949312, 30290151, 19494034, 21185756; Phenotypes: Saul-Wilson syndrome, OMIM #618150, Congenital disorder of glycosylation, type IIj, OMIM #613489; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.89 STARD7 Rebecca Foulger changed review comment from: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.; to: Comment on list classification: Added gene as Amber based on advice from Genomics England Clinical team: the causative variants are the repeat expansion, and therefore the STR will be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
COVID-19 research v1.3 TRBC1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: TRBC1.
COVID-19 research v1.3 KIR2DL2 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: KIR2DL2.
Tag ensembl_ids_known_missing tag was added to gene: KIR2DL2.
COVID-19 research v1.3 KIR2DL2 Eleanor Williams gene: KIR2DL2 was added
gene: KIR2DL2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: KIR2DL2 was set to Unknown
COVID-19 research v1.2 TRBC1 Eleanor Williams gene: TRBC1 was added
gene: TRBC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TRBC1 was set to Unknown
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Classified gene: SRPX2 as Red List (low evidence)
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Added comment: Comment on list classification: Based evidence that the gene / disease associate has been refuted (PMID 24995671).
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Gene: srpx2 has been classified as Red List (Low Evidence).
Intellectual disability v3.80 TTC5 Zornitza Stark reviewed gene: TTC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 32439809; Phenotypes: Central hypotonia, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology, Microcephaly, Abnormality of the face, Behavioral abnormality, Abnormality of the genitourinary system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.80 HIST1H4J Zornitza Stark gene: HIST1H4J was added
gene: HIST1H4J was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4J were set to 31804630
Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features
Review for gene: HIST1H4J was set to AMBER
Added comment: Single case report but with functional evidence in zebrafish and phenotypic similarity to HIST1H4C phenotype
Sources: Literature
Arthrogryposis v3.11 TOR1AIP1 Zornitza Stark reviewed gene: TOR1AIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24856141, 31299614, 30723199, 27342937, 32055997; Phenotypes: Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072, Progeroid appearance, Cataracts, Microcephaly, Deafness, Contractures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hydrocephalus v2.5 TRIM71 Zornitza Stark gene: TRIM71 was added
gene: TRIM71 was added to Hydrocephalus. Sources: Literature
Mode of inheritance for gene: TRIM71 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM71 were set to 29983323; 32168371; 30975633
Phenotypes for gene: TRIM71 were set to Hydrocephalus, congenital communicating, 1, MIM# 618667
Review for gene: TRIM71 was set to GREEN
Added comment: 3 unrelated individuals with de novo missense and hydrocephalus with ventriculomegaly (p.Arg608His recurrent). One patient then transmitted the variant to an affected child. Functional data.
Sources: Literature
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Classified gene: SNX27 as Green List (high evidence)
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited on 05/23/2012) or in Gen2Phen. However, five variants in three unrelated cases (displaying seizures), together with supportive functional studies and mouse model.
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Gene: snx27 has been classified as Green List (High Evidence).
Intellectual disability v3.80 SNX27 Sarah Leigh Classified gene: SNX27 as Green List (high evidence)
Intellectual disability v3.80 SNX27 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited on 05/23/2012) or in Gen2Phen. However, five variants in three unrelated cases, together with supportive functional studies and mouse model.
Intellectual disability v3.80 SNX27 Sarah Leigh Gene: snx27 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.14 CNP Zornitza Stark gene: CNP was added
gene: CNP was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: CNP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNP were set to 32128616; 12590258
Phenotypes for gene: CNP were set to Hypomyelinating leukodystrophy
Review for gene: CNP was set to AMBER
Added comment: Single consanguineous family described with homozygous missense in affected child (additional two affected deceased offspring unavailable for testing; healthy carrier parents and sibling).
Loss of protein by Western blot and defect in F-actin structure and organization observed in patient fibroblasts.
Deficiency of CNP in mouse has previously been shown to cause a lethal white matter neurodegenerative phenotype (PMID: 12590258), similar to the phenotype observed in this family.
Sources: Literature
Arthrogryposis v3.11 SCYL2 Zornitza Stark gene: SCYL2 was added
gene: SCYL2 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: SCYL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL2 were set to 31960134; 26203146
Phenotypes for gene: SCYL2 were set to Arthrogryposis multiplex congenita (AMC); Zain syndrome
Review for gene: SCYL2 was set to AMBER
Added comment: 2 unrelated consanguineous families reported with AMC. Constitutive mouse knockout of Scyl2 results in neonatal lethality and severe motor and sensory deficits.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v2.4 EFEMP1 Zornitza Stark gene: EFEMP1 was added
gene: EFEMP1 was added to Ehlers Danlos syndromes. Sources: Literature
Mode of inheritance for gene: EFEMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFEMP1 were set to 32006683; 31792352
Phenotypes for gene: EFEMP1 were set to Connective tissue disorder
Review for gene: EFEMP1 was set to AMBER
Added comment: Monoallelic variants in this gene are associated with a retinal dystrophy. New publications linking bi-allelic variants to a connective tissue disease phenotype:

PMID 31792352 reports one individual with a pronounced connective tissue phenotype presenting multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin. This individual has no clinical signs of retinal dystrophy.

PMID 32006683 reports 2 homozygous siblings (consanguinous) with multiple and recurrent herniae, pelvic and rectal prolapse, huge diverticula, marfanoid habitus, joint laxity, dorsal scoliosis, advanced bone age, pectus excavatum, dysmorphic facial features, and myopia.

Both papers mention that studies on EFEMP1−/− mice revealed a phenotypic resemblance.
Sources: Literature
Lipodystrophy - childhood onset v2.5 POLR3GL Zornitza Stark gene: POLR3GL was added
gene: POLR3GL was added to Lipodystrophy - childhood onset. Sources: Literature
Mode of inheritance for gene: POLR3GL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3GL were set to 31089205; 31695177
Phenotypes for gene: POLR3GL were set to endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy
Review for gene: POLR3GL was set to AMBER
Added comment: Biallelic canonical splice variants identified in monozygotic twins and another individual with similar phenotypes from 2 unrelated families. RNA studies confirmed exon skipping occurs in all affected individuals.

A separate study identified a homozygous nonsense variant in an individual with features of Neonatal progeroid syndrome/Wiedemann–Rautenstrauch syndrome. Quantitative PCR showed reduction in mRNA suggestive of NMD.

Three cases altogether but the phenotypes are very different -- may represent a spectrum with the more severe phenotypes resulting from truncating variants but further cases needed.
Sources: Literature
Monogenic hearing loss v2.18 SLC12A2 Zornitza Stark reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32294086; Phenotypes: Congenital, severe to profound hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.79 SOX6 Zornitza Stark gene: SOX6 was added
gene: SOX6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SOX6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX6 were set to 32442410
Phenotypes for gene: SOX6 were set to intellectual diability; ADHD; Craniosynostosis; Osteochondromas
Review for gene: SOX6 was set to GREEN
gene: SOX6 was marked as current diagnostic
Added comment: 19 individuals from 17 families with a neurodevelopmental syndrome reported. 6 LoF, 4 missense, and 6 intragenic deletion variants identified. ID ranged from mild to severe.
Sources: Literature
Ophthalmological ciliopathies v1.4 KIF3B Zornitza Stark gene: KIF3B was added
gene: KIF3B was added to Ophthalmological ciliopathies. Sources: Literature
Mode of inheritance for gene: KIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF3B were set to 32386558
Phenotypes for gene: KIF3B were set to hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly
Review for gene: KIF3B was set to AMBER
Added comment: Two unrelated families with a ciliopathy phenotype including RP and some functional data.
Sources: Literature
Hereditary neuropathy or pain disorder v1.4 SORD Zornitza Stark gene: SORD was added
gene: SORD was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to 32367058
Phenotypes for gene: SORD were set to Neuropathy
Review for gene: SORD was set to GREEN
gene: SORD was marked as current diagnostic
Added comment: 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG
(p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state .
Sources: Literature
Childhood solid tumours cancer susceptibility v1.6 ELP1 Zornitza Stark gene: ELP1 was added
gene: ELP1 was added to Childhood solid tumours cancer susceptibility. Sources: Literature
Mode of inheritance for gene: ELP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELP1 were set to 32296180
Phenotypes for gene: ELP1 were set to Paediatric medulloblastoma Sonic Hedgehog subtype
Review for gene: ELP1 was set to GREEN
gene: ELP1 was marked as current diagnostic
Added comment: Medulloblastoma predisposition: association identified for heterozygous ELP1 loss of function variants with paediatric medulloblastoma with exome-wide significance, specifically associated with the sonic hedgehog (SHH) subtype. Association was validated in additional paediatric cohorts. Monoallelic germline loss of function variants identified in 29/202 paediatric medulloblastoma SHH cases (absent from adult patients) and loss of heterozygosity of the ELP1 wild-type allele was present in all tumours.
Sources: Literature
Congenital myopathy v2.5 MYL2 Zornitza Stark gene: MYL2 was added
gene: MYL2 was added to Congenital myopathy. Sources: Expert list
Mode of inheritance for gene: MYL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYL2 were set to 23365102; 27378946
Phenotypes for gene: MYL2 were set to infantile muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy
Review for gene: MYL2 was set to AMBER
Added comment: Monoallelic variants in this gene are a well established as a cause of cardiomyopathy. Thirteen infants from 9 families reported with bi-allelic variants in last exon and an infantile skeletal myopathy/DCM phenotype. Dutch families all had same founder variant; one Italian family had two different variants.
Sources: Expert list
Congenital myopathy v2.5 MYH8 Zornitza Stark reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: 22918376, 17434305; Phenotypes: Trismus-pseudocamptodactyly syndrome MIM#158300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.5 MYF5 Zornitza Stark reviewed gene: MYF5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ophthalmoplegia, external, with rib and vertebral anomalies 618155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v1.1 DAG1 Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007).

PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection.

PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs.

PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses.
Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands.

PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function.
Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis.

PMID 15857984: Kunz et al. (2005)
Show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range.
Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells.
LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding.
LCMV uses the same domains of α-DG for binding that are used in LFV binding.
Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates.; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007).

PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection.

PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs.

PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses.
Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands.

PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function.
Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis.

PMID 15857984: Kunz et al. (2005) show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells.
LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding.
LCMV uses the same domains of α-DG for binding that are used in LFV binding.
Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates.
Early onset or syndromic epilepsy v2.87 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to 31754459; 27904971
Likely inborn error of metabolism v2.10 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Green List (high evidence)
Likely inborn error of metabolism v2.10 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Based on five variants in three unrelated cases, together with supportive aminal model studies.
Likely inborn error of metabolism v2.10 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Green List (High Evidence).
Intellectual disability v3.79 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Green List (high evidence)
Intellectual disability v3.79 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 5 variants published in three unrelated famililies (4 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies (PMID 29669219; 23104561). One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459), another case had brain, immune, bone and intestinal dysfunction (PMID 27904971) and the third had metabolic dysfunction mimicking biotinidase deficiency (PMID 31392107). This condition could be treated with biotin supplementation and introduction of pantothenic acid supplementation (PMID 31392107).
Intellectual disability v3.79 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v2.9 SLC5A6 Sarah Leigh gene: SLC5A6 was added
gene: SLC5A6 was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219
Phenotypes for gene: SLC5A6 were set to SLC5A6-related Neurodevelopmental Disorder
Review for gene: SLC5A6 was set to GREEN
Added comment: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 5 variants published in three unrelated famililies (4 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies (PMID 29669219; 23104561). One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459), another case had brain, immune, bone and intestinal dysfunction (PMID 27904971) and the third had metabolic dysfunction mimicking biotinidase deficiency (PMID 31392107). This condition could be treated with biotin supplementation and introduction of pantothenic acid supplementation (PMID 31392107).
Sources: Literature
Early onset or syndromic epilepsy v2.86 SLC5A6 Sarah Leigh Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to SLC5A6-related Neurodevelopmental Disorder
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 4 variants published in two unrelated famililies (3 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies. One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459).
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.78 CXorf56 Sarah Leigh Tag Skewed X-inactivation tag was added to gene: CXorf56.
Intellectual disability v3.78 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.84 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
DDG2P v2.8 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
White matter disorders and cerebral calcification - narrow panel v1.14 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.7 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
COVID-19 research v1.1 LDLR Sarah Leigh edited their review of gene: LDLR: Added comment: Loss of LDLR from the cell surface results in resistance to viral infection (PMID 10535997, 31386864, 31358055).; Changed rating: RED
COVID-19 research v1.1 HLA-DRB5 Rebecca Foulger commented on gene: HLA-DRB5
COVID-19 research v1.1 HLA-DRA Rebecca Foulger commented on gene: HLA-DRA
COVID-19 research v1.1 HLA-DPB1 Rebecca Foulger commented on gene: HLA-DPB1
COVID-19 research v1.1 HLA-A Rebecca Foulger commented on gene: HLA-A
COVID-19 research v1.1 CCL21 Rebecca Foulger commented on gene: CCL21
COVID-19 research v1.1 GC Rebecca Foulger commented on gene: GC
COVID-19 research v1.1 FUT2 Rebecca Foulger commented on gene: FUT2
COVID-19 research v1.1 CLEC4M Rebecca Foulger commented on gene: CLEC4M
COVID-19 research v1.1 IL7 Rebecca Foulger commented on gene: IL7
COVID-19 research v1.1 HLA-DRB5 Rebecca Foulger gene: HLA-DRB5 was added
gene: HLA-DRB5 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: HLA-DRB5 was set to Unknown
COVID-19 research v1.1 HLA-DRA Rebecca Foulger gene: HLA-DRA was added
gene: HLA-DRA was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: HLA-DRA was set to Unknown
COVID-19 research v1.1 HLA-DPB1 Rebecca Foulger gene: HLA-DPB1 was added
gene: HLA-DPB1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: HLA-DPB1 was set to Unknown
Phenotypes for gene: HLA-DPB1 were set to {Beryllium disease, chronic, susceptibility to}
COVID-19 research v1.1 HLA-A Rebecca Foulger gene: HLA-A was added
gene: HLA-A was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: HLA-A was set to Unknown
Phenotypes for gene: HLA-A were set to {Hypersensitivity syndrome, carbamazepine-induced, susceptibility to}, 608579
COVID-19 research v1.1 CCL21 Rebecca Foulger gene: CCL21 was added
gene: CCL21 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CCL21 was set to Unknown
COVID-19 research v1.1 GC Rebecca Foulger gene: GC was added
gene: GC was added to COVID-19 research. Sources: OMIM,Expert list,Expert Review Amber
Mode of inheritance for gene: GC was set to Unknown
COVID-19 research v1.1 FUT2 Rebecca Foulger gene: FUT2 was added
gene: FUT2 was added to COVID-19 research. Sources: OMIM,Expert list,Expert Review Amber
Mode of inheritance for gene: FUT2 was set to Unknown
Phenotypes for gene: FUT2 were set to {Norwalk virus infection, resistance to}
COVID-19 research v1.1 CLEC4M Rebecca Foulger gene: CLEC4M was added
gene: CLEC4M was added to COVID-19 research. Sources: OMIM,Expert list,Expert Review Amber
Mode of inheritance for gene: CLEC4M was set to Unknown
Phenotypes for gene: CLEC4M were set to SARS infection, protection against, 605872
COVID-19 research v1.1 IL7 Rebecca Foulger gene: IL7 was added
gene: IL7 was added to COVID-19 research. Sources: OMIM,Expert list,Expert Review Amber
Mode of inheritance for gene: IL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL7 were set to 25981006
Phenotypes for gene: IL7 were set to {?Epidermodysplasia verruciformis, susceptibility to, 5}, 618309
Childhood onset dystonia, chorea or related movement disorder v1.4 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Intellectual disability v3.78 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Early onset or syndromic epilepsy v2.84 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Clefting v2.3 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
DDG2P v2.8 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Fetal anomalies v1.73 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Likely inborn error of metabolism v2.8 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Undiagnosed metabolic disorders v1.414 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Thrombophilia with a likely monogenic cause v1.4 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Cytopenias and congenital anaemias v1.73 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Inherited bleeding disorders v1.156 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Congenital disorders of glycosylation v2.6 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Hereditary neuropathy or pain disorder v1.4 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Paediatric or syndromic cardiomyopathy v1.5 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Retinal disorders v2.13 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Intellectual disability v3.78 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Monogenic hearing loss v2.18 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Hereditary neuropathy v1.368 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
DDG2P v2.8 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Fetal anomalies v1.73 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Dilated and arrhythmogenic cardiomyopathy v1.3 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.6 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Arthrogryposis v3.11 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Congenital muscular dystrophy v2.4 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Dilated Cardiomyopathy and conduction defects v1.65 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Gastrointestinal neuromuscular disorders v1.12 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
COVID-19 research v1.0 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Distal myopathies v1.20 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
Laterality disorders and isomerism v1.5 FOXJ1 Zornitza Stark gene: FOXJ1 was added
gene: FOXJ1 was added to Laterality disorders and isomerism. Sources: Expert list
Mode of inheritance for gene: FOXJ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXJ1 were set to 31630787
Phenotypes for gene: FOXJ1 were set to Hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry
Review for gene: FOXJ1 was set to GREEN
gene: FOXJ1 was marked as current diagnostic
Added comment: PMID 31630787 - Six unrelated individuals with de novo variants in this gene. Patients have hydrocephaly, bronchiectasis and respiratory disease. Situs inversus was shown in 3/6 patients.
Electron microscopy of demonstrated cilia were unable to general fluid flow and were less frequent on cells. All reported variants were truncating mutations affecting the last exon in the protein, therefore loss of function is less likely the mechanism of pathogenicity
Sources: Expert list
Laterality disorders and isomerism v1.5 FANCB Zornitza Stark reviewed gene: FANCB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anemia, complementation group B, MIM# 300514; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.5 ACTG2 Zornitza Stark reviewed gene: ACTG2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Visceral myopathy, MIM# 155310; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Laterality disorders and isomerism v1.5 ACTC1 Zornitza Stark reviewed gene: ACTC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 5, MIM# 612794; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.78 TTC5 Konstantinos Varvagiannis gene: TTC5 was added
gene: TTC5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC5 were set to 29302074; 32439809
Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Penetrance for gene: TTC5 were set to Complete
Review for gene: TTC5 was set to GREEN
Added comment: Hu et al (2019 - PMID: 29302074) reported briefly on 3 individuals from 2 consanguineous families (from Turkey and Iran) with biallelic TTC5 variants. Features included DD (3/3), ID (severe in 2/2 with relevant age), microcephaly (3/3), brain abnormalities, etc. A nonsense and a variant affecting splice site were identified by WES/WGS.

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In a recent report, Rasheed et al (2020 - PMID: 32439809) report on the phenotype of 8 individuals - belonging to 5 consanguineous families - all 8 harboring homozygous TTC5 mutations.

Frequent features included hypotonia (6/8), motor and speech delay, moderate to severe ID (10/10 of relevant age - inclusion of less severely affected subjects was not considered by study design), brain MRI abnormalities (8/8). Other findings included microcephaly in some (6/11), behavioral abnormalities in few (autistic behavior in 2/8, aggression in 2/8), genitourinary anomalies (2/8), seizures (1/11). Facial phenotype incl. thin V-shaped upper lip, low-set ears (in most) and/or additional features.

TTC5 encodes a 440 aa protein, functioning as a scaffold to stabilise p300-JMY interactions. Apart from this role in nucleus, it has functions in the cytoplasm (inhibiting actin nucleataion, autophagosome formation, etc).

The gene has ubiquitous expression, highest in brain.

All variants were identified following WES - as the best candidates - in affected individuals with compatible Sanger studies in all affected family members and carrier parents.

2 missense and 2 nonsense variants were identified with the 2 missense SNVs localizing within TPR domains. qRT-PCR studies for a nonsense variant localizing 19 nt before the last exon, revealed fourfold decreased expression in affected individuals compared to carriers.

Families from Egypt shared a homozygous ~6.3 Mb haplotype block spanning TTC5, suggesting that p.(Arg263Ter) is likely a founder mutation.

The authors underscore some phenotypic (though not facial) similarities with Rubinstein-Taybi syndrome 2 due to EP300 mutations (in line with the role of TTC5).

Biallelic variants in genes encoding other members of the TTC family (containing a TPR motif), e.g. TTC8 or TTC15 cause disorders with neurologic manifestations (and DD/ID).
Sources: Literature
Intellectual disability v3.78 AGMO Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.; to: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression) and therefore this is borderline. Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One homozygous case presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.; to: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One family presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger Classified gene: AGMO as Amber List (moderate evidence)
Intellectual disability v3.78 AGMO Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Zornitza Stark. One homozygous case presented in PMID:27000257, and 2 compound het cases in PMID:31555905 (though there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant). Functional data shows decreased enzyme activity of the variants. Although there are 3 cases, the phenotype is variable between patients (ID/DD vs regression). Therefore, rated as Amber awaiting further cases and clinical opinion.
Intellectual disability v3.78 AGMO Rebecca Foulger Gene: agmo has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.77 AGMO Rebecca Foulger changed review comment from: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family. Epilepsy is not mentioned amongst their phenotypes.; to: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family.
Intellectual disability v3.77 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) was reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) were reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Classified gene: SETD5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Added comment: Comment on list classification: Review article PMID 29484850 reports seizures in 10/42 (23.8%) cases of autism spectrum disorders carrying heterozygous SETD5 variants.
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Gene: setd5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.83 SETD5 Sarah Leigh Publications for gene: SETD5 were set to 25138099; 24680889
Intellectual disability v3.77 AGMO Rebecca Foulger Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to microcephaly; intellectual disability; epilepsy; developmental delay
Intellectual disability v3.77 AGMO Rebecca Foulger Publications for gene: AGMO were set to 31555905
Intellectual disability v3.76 AGMO Rebecca Foulger commented on gene: AGMO: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals (8 year old European girl, and 4-year old Ashkenazi Jewish boy). They demonstrated significantly diminished enzyme activity for all disease-associated variants. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions MTHFR C677T homozygous for the boy, but this is not referred to within the text. ID/DD (and seizures) was reported in the girl. The boy showed normal development to begin, but began to regress age 3.5 years.
Intellectual disability v3.76 AGMO Rebecca Foulger commented on gene: AGMO
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger changed review comment from: PMID:27000257. Alrayes et al., 2016 report a homozygous frameshift variant in AGMO- p.(Glu324LysfsTer12) in 2 brothers from a consanguineous Saudi family with syndromic microcephaly, and global developmental delay. Epilepsy is not mentioned amongst their phenotypes.; to: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family. Epilepsy is not mentioned amongst their phenotypes.
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Classified gene: AGMO as Red List (low evidence)
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Amber by Zornitza Stark. Only 1 of the 3 individuals from PMIDs:31555905 and 27000257 is reported with epilepsy. Therefore rated Red awaiting further evidence.
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Gene: agmo has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl had variants p.Trp130Ter & p.Gly238Cys. The boy had variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. They demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl had variants p.Trp130Ter & p.Gly238Cys. The boy had variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger commented on gene: AGMO: PMID:27000257. Alrayes et al., 2016 report a homozygous frameshift variant in AGMO- p.(Glu324LysfsTer12) in 2 brothers from a consanguineous Saudi family with syndromic microcephaly, and global developmental delay. Epilepsy is not mentioned amongst their phenotypes.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to microcephaly; intellectual disability; epilepsy; generalized tonic-clonic seizures
Early onset or syndromic epilepsy v2.80 AGMO Rebecca Foulger commented on gene: AGMO
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype.; to: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype. Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Classified gene: SEMA6B as Green List (high evidence)
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype.
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Gene: sema6b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.79 SEMA6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: The authors of PMID:32169168 suggest a dominant-negative or gain-of-function effect rather than haploinsufficiency.
Early onset or syndromic epilepsy v2.79 SEMA6B Rebecca Foulger Mode of pathogenicity for gene: SEMA6B was changed from None to Other
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger changed review comment from: PMID:32169168. In 4 unrelated patients (2 Japanese, ISraeli and Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.; to: PMID:32169168. In 4 unrelated patients (2 Japanese, 1 Israeli and 1 Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger commented on gene: SEMA6B
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger Phenotypes for gene: SEMA6B were changed from Progressive myoclonic epilepsy to Epilepsy, progressive myoclonic, 11, 618876
Intellectual disability v3.76 KAT8 Rebecca Foulger Tag missense tag was added to gene: KAT8.
Intellectual disability v3.76 KAT8 Rebecca Foulger commented on gene: KAT8: Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Intellectual disability v3.76 KAT8 Rebecca Foulger Mode of pathogenicity for gene: KAT8 was changed from None to Other
Intellectual disability v3.75 KAT8 Rebecca Foulger Added comment: Comment on mode of inheritance: Individual T9 inherited biallelc variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. This is the only example of biallelic inheritance, so have set MOI to 'monoallelic' until more cases are identified.
Intellectual disability v3.75 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.74 KAT8 Rebecca Foulger Classified gene: KAT8 as Green List (high evidence)
Intellectual disability v3.74 KAT8 Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). All individuals had DD and/or ID (Supplementary materials). Knockout mice failed to thrive, and showed early lethality and cerebral hypoplasia.
Intellectual disability v3.74 KAT8 Rebecca Foulger Gene: kat8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.77 KAT8 Rebecca Foulger Mode of pathogenicity for gene: KAT8 was changed from None to Other
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger Tag missense tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger commented on gene: KAT8: Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.; to: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.75 KAT8 Rebecca Foulger Added comment: Comment on mode of inheritance: Individual T9 inherited biallelic variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. Since this is the only example of biallelic variants so far, I have set the MOI to 'monoallelic'.
Early onset or syndromic epilepsy v2.75 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Classified gene: KAT8 as Green List (high evidence)
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Gene: kat8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Tag watchlist was removed from gene: TIMM50.
Tag for-review tag was added to gene: TIMM50.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger commented on gene: TIMM50: Removed 'watchlist' tag, since this gene is no longer Amber. Note that TIMM50 is Green on the Intellectual disability panel (V3.73) and on the IEM panel (V2.8). Therefore added 'for-review' tag for discussion of alignment of epilepsy and metabolism panels.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Deleted their comment
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Classified gene: TIMM50 as Green List (high evidence)
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Added comment: Comment on list classification: Previous Amber rating was based on insufficient evidence (PMID:27573165/Shahrour et al 2017 who report 4 cases from 2 consanguineous families, plus a conference abstract reporting 3 further siblings). Zornitza Stark and Konstantinos Varvagiannis point out 2 new papers each with an additional case of TIMM50 variants in epileptic patients. Therefore have updated the rating from Amber to Green.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Gene: timm50 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.72 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX, 617698; intellectual disability and seizure; epilepsy and developmental delay to 3-methylglutaconic aciduria, type IX, 617698; intellectual disability and seizure; epilepsy and developmental delay; epileptic encephalopathy
Early onset or syndromic epilepsy v2.71 TIMM50 Rebecca Foulger Publications for gene: TIMM50 were set to 27573165; Serajee F, Hu A. A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene. ASHG meeting 2015 Abstract Nr 2299, 2015.
Early onset or syndromic epilepsy v2.70 TIMM50 Rebecca Foulger Added comment: Comment on publications: 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T)
Early onset or syndromic epilepsy v2.70 TIMM50 Rebecca Foulger Publications for gene: TIMM50 were set to 27573165; Serajee F, Hu A. A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene. ASHG meeting 2015 Abstract Nr 2299, 2015.
Early onset or syndromic epilepsy v2.69 TIMM50 Rebecca Foulger commented on gene: TIMM50: PMID:31058414 (Tort et al., 2019) report compound het TIMM50 variants in a boy with 3-MGA-uria (p.Arg114Gln, p.Gly269Ser). At 3.5 months, a diagnosis of West syndrome was made, and he showed a good response to ACTH and antiepileptic treatment.
Early onset or syndromic epilepsy v2.69 TIMM50 Rebecca Foulger commented on gene: TIMM50: PMID:30190335. Reyes et al., 2018 report a third unrelated family. WES identified compound het pathogenic TIMM50 variants (p.S112* and p.G190A) in an infant with rapidly progressive, severe encephalopathy, including infantile seizures and severe epilepsy. Sanger sequencing confirmed the two variants in the proband and showed that the two parents were each heterozygous for one of them. In the ExAc database, the p.G190A variant was present in <200,000 alleles, with the nonsense change not reported.
Long QT syndrome v2.6 TRDN Zornitza Stark gene: TRDN was added
gene: TRDN was added to Long QT syndrome. Sources: Expert list
Mode of inheritance for gene: TRDN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRDN were set to 31983240; 25922419
Phenotypes for gene: TRDN were set to Long QT syndrome
Review for gene: TRDN was set to GREEN
Added comment: Gene-disease association rated as DEFINITIVE by ClinGen:
Evidence for involvement of TRDN in LQTS was based mainly on a single publication demonstrating 5 cases with homozygous or compound heterozygous frameshift variants. All cases presented during early childhood (up to the age of 3 years) with QT prolongation, negative T waves in precordial leads, and exercise-induced arrhythmias, although typical
torsades de pointes was demonstrated only in 1 case. Experimental evidence demonstrated that TRDN loss of function may lead to arrhythmogenesis but did not specifically show prolongation of repolarization, which is the hallmark of LQTS. Accordingly, there was a debate
within the panel as to whether the TRDN-related cardiac phenotype should be classified as CPVT or as a unique syndrome, referred in the literature as triadin knockout syndrome. Because QT prolongation was the most easily discernable abnormality, it was decided to consider these cases as having an atypical LQTS phenotype. Furthermore, it was agreed that there was strong evidence for TRDN’s disease association.
Sources: Expert list
Long QT syndrome v2.6 KCNE2 Zornitza Stark reviewed gene: KCNE2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 6, MIM# 613693; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Long QT syndrome v2.6 KCNE1 Zornitza Stark reviewed gene: KCNE1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Jervell and Lange-Nielsen syndrome 2, MIM# 612347, Long QT syndrome 5, MIM# 613695; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.5 NKX2-5 Zornitza Stark reviewed gene: NKX2-5: Rating: RED; Mode of pathogenicity: None; Publications: 25742962, 26805889; Phenotypes: Ventricular septal defect 3 (MIM#614432), Tetralogy of Fallot (MIM#187500); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Laterality disorders and isomerism v1.5 CCDC65 Zornitza Stark reviewed gene: CCDC65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23991085, 24094744; Phenotypes: Ciliary dyskinesia, primary, 27, MIM# 615504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.5 CFC1 Zornitza Stark reviewed gene: CFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31633655, 18162845, 25423076, 11062482; Phenotypes: Heterotaxy, visceral, 2, autosomal 605376; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Laterality disorders and isomerism v1.5 DNAAF2 Zornitza Stark reviewed gene: DNAAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19052621, 31107948; Phenotypes: Ciliary dyskinesia, primary, 10 612518; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.5 DNAH6 Zornitza Stark gene: DNAH6 was added
gene: DNAH6 was added to Laterality disorders and isomerism. Sources: Expert list
Mode of inheritance for gene: DNAH6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH6 were set to 26918822
Phenotypes for gene: DNAH6 were set to Heterotaxy; male infertility
Review for gene: DNAH6 was set to AMBER
Added comment: PMID: 26918822 - zebrafish model has disrupted motile cilia and cilia length, with some body axis defects within embryos. Transfected human cells also had defective motile cilia and cilia width. Two patients with heterotaxy, one homozygous (missense), the other heterozygous (missense), but the heterozygous carrier has an additional known PCD mutation in DNA1. Summary: 1 convincing patient with animal model
Sources: Expert list
Laterality disorders and isomerism v1.5 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: RED; Mode of pathogenicity: None; Publications: 20656787, 29969989, 15735645; Phenotypes: Atrial septal defect 3 (MIM#614089); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.73 NUP88 Julia Baptista gene: NUP88 was added
gene: NUP88 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NUP88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP88 were set to PMID: 30543681
Phenotypes for gene: NUP88 were set to fetal akinesia
Review for gene: NUP88 was set to RED
Added comment: Bonnin et al reported biallelic variants in two unrelated families.
A homozygous missense variant was identified in family A and the co-segregation data was supportive (tested 4 unaffected and 2 of the 4 affected fetuses). Compound heterozygous in-frame and nonsense variants were identified in the proband in family B (co-segregation studies in 2 unaffected sibs). The clinical features included fetal akinesia and arthrogryposis multiplex congenita. Polyhydramnios, muscle atrophy and dysmorphic features were also described.
Sources: Literature
COVID-19 research v1.0 Catherine Snow promoted panel to version 1.0
COVID-19 research v0.377 CD200 Sarah Leigh Publications for gene: CD200 were set to 19587022
COVID-19 research v0.376 CD200 Sarah Leigh Classified gene: CD200 as Red List (low evidence)
COVID-19 research v0.376 CD200 Sarah Leigh Added comment: Comment on list classification: Not associated with a phenotype in OMIM or in Gen2Phen. However, CD200 is a membrane protein that interacts with CD200R on the surface of immune cells and delivers an inhibitory signal to suppress immune functions as a "check point" to prevent an excessive inflammatory response . Viral homologs of CD200, such as rat cytomegalovirus e127 protein, may play a role in suppressing the host immune response (PMID 19587022).
Conversely, in coronavirus infection, inhibition of CD200-CD200R1 results in restoring IFN production and increasing virus clearance (PMID 30032349).
Therefore understanding of the mechanisms of CD200-CD200R action may help in development of treatments.
COVID-19 research v0.376 CD200 Sarah Leigh Gene: cd200 has been classified as Red List (Low Evidence).
COVID-19 research v0.375 CD200 Sarah Leigh Publications for gene: CD200 were set to
COVID-19 research v0.374 CD200 Sarah Leigh reviewed gene: CD200: Rating: ; Mode of pathogenicity: None; Publications: 19587022; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.374 IRF5 Rebecca Foulger Classified gene: IRF5 as Green List (high evidence)
COVID-19 research v0.374 IRF5 Rebecca Foulger Added comment: Comment on list classification: Green rating suggested after initial triage by Illumina curation team. Kept rating as Green following literature review: PMID:29375210 demonstrate that polymorphisms in IRF5 can affect viral disease progression. Functional studies and animal models (fish and mice) show that IRF5 is required for antiviral immunity. Therefore on balance, kept rating as Green.
COVID-19 research v0.374 IRF5 Rebecca Foulger Gene: irf5 has been classified as Green List (High Evidence).
COVID-19 research v0.373 IRF5 Rebecca Foulger commented on gene: IRF5: PMID:30457675. Chow et al., 2019 examined IRF5-dependent gene expression and found that loss of IRF5 in mice resulted in modest and subtle changes in the expression of West Nile Virus (WNV)-regulated genes.
15320958
COVID-19 research v0.373 IRF5 Rebecca Foulger commented on gene: IRF5: PMID:21240265. Krausgruber et al., 2011 state that polymorphisms in IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively, defining a role for IRF5 as a transcriptional repressor.
COVID-19 research v0.373 IRF5 Rebecca Foulger commented on gene: IRF5: PMID:29079574. Cevik et al., 2017 identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
COVID-19 research v0.373 IRF5 Rebecca Foulger commented on gene: IRF5: PMID:29375210. Sy et al., 2018 investigated possible effects of IRF5 polymorphisms in the 3' UTR region of the IFR5 locus on susceptibility to hepatitis B virus (HBV) infection and liver disease outcomes. Comparing patients and controls, no significant association was observed in viral load for the four IFR5 variants studied, but alleles rs13242262T and rs10488630G contributed to an increased risk of liver cirrhosis. The process of liver cirrhosis in HBV infection is a results of the interplay between viral factors and host immune responses suggesting that IRF5 haplotypes appear to influence the outcome of HBV infection.
COVID-19 research v0.373 IRF5 Rebecca Foulger commented on gene: IRF5: PMID:32075938. Forbester et al., 2020 use human-induced pluripotent stem cells (hIPSCs) with biallelic mutations in IRF5, and showed that IRF5 deficiency corresponded with reduced influenza virus-induced inflammatory cytokine production.
COVID-19 research v0.373 IRF5 Rebecca Foulger commented on gene: IRF5: PMID:17360658. Yanai et al., 2007. Mouse model: authors show that IRF5 is critical for antiviral immunity by showing that Irf5(-/-) mice are highly vulnerable to viral infections.
COVID-19 research v0.373 IRF5 Rebecca Foulger Publications for gene: IRF5 were set to 17360658; 32075938; 29375210; 29079574; 1240265; 30457675
COVID-19 research v0.372 IRF5 Rebecca Foulger Publications for gene: IRF5 were set to
COVID-19 research v0.371 TNFSF10 Rebecca Foulger Classified gene: TNFSF10 as Amber List (moderate evidence)
COVID-19 research v0.371 TNFSF10 Rebecca Foulger Added comment: Comment on list classification: Kept the Amber rating initially suggested by Illumina curation team: plays a role in viral surveillance, and virus can modulate TNFSF10 (TRAIL) signaling. Many studies look at expression levels following infection. No direct susceptibility studies, so Amber appropriate.
COVID-19 research v0.371 TNFSF10 Rebecca Foulger Gene: tnfsf10 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.370 TNFSF10 Rebecca Foulger Publications for gene: TNFSF10 were set to 18802095; 14702109; 31725732; 27740879; 17913827; 15110181
COVID-19 research v0.369 TNFSF10 Rebecca Foulger changed review comment from: Summary of literature: TNFSF10/TRAIL is a death ligand that contributes to immune surveillance against virus-infected cells via the death receptor TNFRSF10B/DR5. TNFSF10 binding induces the caspase cascade to kill the virus-infected cell. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling.; to: Summary of literature: TNFSF10/TRAIL is a death ligand that contributes to immune surveillance against virus-infected cells via the death receptor DR5. TNFSF10 binding induces the caspase cascade to kill the virus-infected cell. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling.
COVID-19 research v0.369 TNFSF10 Rebecca Foulger commented on gene: TNFSF10: Summary of literature: TNFSF10/TRAIL is a death ligand that contributes to immune surveillance against virus-infected cells via the death receptor TNFRSF10B/DR5. TNFSF10 binding induces the caspase cascade to kill the virus-infected cell. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling.
COVID-19 research v0.369 VPS4A Sarah Leigh Publications for gene: VPS4A were set to
COVID-19 research v0.368 VPS4A Sarah Leigh reviewed gene: VPS4A: Rating: ; Mode of pathogenicity: None; Publications: 17928862, 30615963; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.368 TNFSF10 Rebecca Foulger Publications for gene: TNFSF10 were set to 18802095; 14702109
COVID-19 research v0.367 TPH1 Sarah Leigh Publications for gene: TPH1 were set to
COVID-19 research v0.366 TPH1 Sarah Leigh changed review comment from: TPH1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
Using lymphocytic choriomeningitis virus in a Cd8-positive T cell-dependent mouse model of immunopathologic hepatitis, PMID 18516052 showed that Tph1-deficient mice, but not wildtype mice, normalized hepatic microcirculatory dysfunction, accelerated clearance of virus from liver, and reduced Cd8-positive T cell-dependent liver cell damage (reviewed by Alison Coffey and team, Illumina).; to: TPH1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
TPH1 is part of the pathway for the synthesis of the neurotrasmitter serotonin.
Using lymphocytic choriomeningitis virus in a Cd8-positive T cell-dependent mouse model of immunopathologic hepatitis, PMID 18516052 showed that Tph1-deficient mice, but not wildtype mice, normalized hepatic microcirculatory dysfunction, accelerated clearance of virus from liver, and reduced Cd8-positive T cell-dependent liver cell damage, therefore it has been concluded that vasoactive serotonin supports virus persistence in liver and aggravates virus-induced immunopathology. (reviewed by Alison Coffey and team, Illumina).
COVID-19 research v0.366 TPH1 Sarah Leigh Classified gene: TPH1 as Red List (low evidence)
COVID-19 research v0.366 TPH1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or in Gen2Phen.
COVID-19 research v0.366 TPH1 Sarah Leigh Gene: tph1 has been classified as Red List (Low Evidence).
COVID-19 research v0.365 TPH1 Sarah Leigh reviewed gene: TPH1: Rating: ; Mode of pathogenicity: None; Publications: 18516052; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.365 TNFSF4 Sarah Leigh changed review comment from: TNFSF4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
Tumor necrosis factor (TNF) family cytokines function as prominent mediators of immune regulation and the inflammatory response. Most TNF family cytokines are expressed as type II transmembrane proteins, with homology confined to approximately 150 C-terminal residues. The TNF ligands interact with a parallel family of receptors (reviewed by Alison Coffey and team, Illumina).
TNFSF4 is a cell surface glycoprotein antigen that is expressed in T-cell leukemia virus type 1 (HTLV-1) infected human cells (PMID 7913952;8076595). Functional analysis showed that anti-TNFSF4 monoclonal antibody inhibited T-cell proliferation (PMID 11359859).; to: TNFSF4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
Tumor necrosis factor (TNF) family cytokines function as prominent mediators of immune regulation and the inflammatory response. Most TNF family cytokines are expressed as type II transmembrane proteins, with homology confined to approximately 150 C-terminal residues. The TNF ligands interact with a parallel family of receptors (reviewed by Alison Coffey and team, Illumina).
TNFSF4 is a cell surface glycoprotein antigen that is expressed in T-cell leukemia virus type 1 (HTLV-1) infected human cells (PMID 7913952;8076595). Functional analysis showed that anti-TNFSF4 monoclonal antibody inhibited T-cell proliferation (PMID 11359859).
PMID 31725732: suggests that TNFSF4, one of the major causative cytokine factors in African swine fever virus pathogenesis, via inducing apoptosis.
COVID-19 research v0.365 TNFSF4 Sarah Leigh Publications for gene: TNFSF4 were set to 7913952; 8076595; 11359859
COVID-19 research v0.364 TLR5 Sarah Leigh changed review comment from: TLR5 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
The transmembrane protein TLR5 is a component of the immune system that is highly expressed in intestinal mucosa and recognizes bacterial flagellin (PMID 20203013)(reviewed by Alison Coffey and team, Illumina).
PMID 25395539 reports that mice treated with bacterial flagellin prevented rotavirus (RV) infection and cured chronically RV-infections. This processed required the flagellin receptors Tlr5 and Nlrc4. Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, resulting in a protective gene expression program in intestinal epithelial cells. Administration of Il22 to mice reproduced the capacity of flagellin to prevent or cure RV. It was proposed that activation of innate immunity with flagellin, via Tlr5 inducing IL22 could be useful in preventing or curing viral infections.; to: TLR5 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
The transmembrane protein TLR5 is a component of the immune system that is highly expressed in intestinal mucosa and recognizes bacterial flagellin (PMID 20203013)(reviewed by Alison Coffey and team, Illumina).
PMID 25395539 reports that mice treated with bacterial flagellin prevented rotavirus (RV) infection and cured chronically RV-infections. This process required the flagellin receptors Tlr5 and Nlrc4. Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, resulting in a protective gene expression program in intestinal epithelial cells. Administration of Il22 to mice reproduced the capacity of flagellin to prevent or cure RV. It was proposed that activation of innate immunity with flagellin, via Tlr5 inducing IL22 could be useful in preventing or curing viral infections.
COVID-19 research v0.364 TLR4 Sarah Leigh changed review comment from: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269).; to: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269).
COVID-19 research v0.364 TLR4 Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.

PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.
PMID 32391647 reports: Hyperactivated B cell and TLR4 signalling pathway were observed in WT HBV-carrier mice, while TLR4 ablation failed to induce B cell hyperactivation, and downstream MyD88 and NF-κB were also not altered. Taken together, TLR4 pathway plays a pivotal role in B cell hyperactivation during CHB, which might serve as a promising target for B cell function restoration.
PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19.
COVID-19 research v0.364 TLR4 Sarah Leigh Publications for gene: TLR4 were set to 11062499; 17579031; 17709532; 32383269
COVID-19 research v0.363 TLR4 Sarah Leigh Publications for gene: TLR4 were set to 11062499; 17579031; 17709532
COVID-19 research v0.362 TLR4 Sarah Leigh changed review comment from: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV).; to: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269).
COVID-19 research v0.362 TLR4 Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.

PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19.
COVID-19 research v0.362 TNFSF4 Sarah Leigh Classified gene: TNFSF4 as Red List (low evidence)
COVID-19 research v0.362 TNFSF4 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or in Gen2Phen.
COVID-19 research v0.362 TNFSF4 Sarah Leigh Gene: tnfsf4 has been classified as Red List (Low Evidence).
COVID-19 research v0.361 TNFSF4 Sarah Leigh commented on gene: TNFSF4
COVID-19 research v0.361 TNFSF4 Sarah Leigh Publications for gene: TNFSF4 were set to 7913952; 8076595
COVID-19 research v0.360 FEZ1 Catherine Snow reviewed gene: FEZ1: Rating: ; Mode of pathogenicity: None; Publications: 31422020, 30815230; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.360 TNFSF4 Sarah Leigh Publications for gene: TNFSF4 were set to
COVID-19 research v0.359 TNFSF10 Rebecca Foulger Publications for gene: TNFSF10 were set to
COVID-19 research v0.358 TLR4 Sarah Leigh Phenotypes for gene: TLR4 were changed from to Susceptibility to respiratory syncytial virus
COVID-19 research v0.357 TLR4 Sarah Leigh Publications for gene: TLR4 were set to
COVID-19 research v0.356 TLR5 Sarah Leigh Publications for gene: TLR5 were set to
COVID-19 research v0.355 TLR5 Sarah Leigh edited their review of gene: TLR5: Added comment: TLR5 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
The transmembrane protein TLR5 is a component of the immune system that is highly expressed in intestinal mucosa and recognizes bacterial flagellin (PMID 20203013)(reviewed by Alison Coffey and team, Illumina).
PMID 25395539 reports that mice treated with bacterial flagellin prevented rotavirus (RV) infection and cured chronically RV-infections. This processed required the flagellin receptors Tlr5 and Nlrc4. Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, resulting in a protective gene expression program in intestinal epithelial cells. Administration of Il22 to mice reproduced the capacity of flagellin to prevent or cure RV. It was proposed that activation of innate immunity with flagellin, via Tlr5 inducing IL22 could be useful in preventing or curing viral infections.; Changed publications: 20203013, 25395539
COVID-19 research v0.355 FCMR Catherine Snow Publications for gene: FCMR were set to
COVID-19 research v0.354 TLR5 Sarah Leigh Classified gene: TLR5 as Red List (low evidence)
COVID-19 research v0.354 TLR5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. However, there is evidence that this gene is associated with the immune response to viral infection (PMID 25395539).
COVID-19 research v0.354 TLR5 Sarah Leigh Gene: tlr5 has been classified as Red List (Low Evidence).
COVID-19 research v0.353 FCMR Catherine Snow reviewed gene: FCMR: Rating: ; Mode of pathogenicity: None; Publications: 32073687, 29461978, 28747342, 23359703; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.353 IRF5 Rebecca Foulger Classified gene: IRF5 as Green List (high evidence)
COVID-19 research v0.353 IRF5 Rebecca Foulger Gene: irf5 has been classified as Green List (High Evidence).
COVID-19 research v0.352 IRF5 Rebecca Foulger commented on gene: IRF5
COVID-19 research v0.352 IRF5 Rebecca Foulger gene: IRF5 was added
gene: IRF5 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: IRF5 was set to Unknown
COVID-19 research v0.351 TLR4 Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.
COVID-19 research v0.351 TLR4 Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.
COVID-19 research v0.351 EIF3M Catherine Snow Publications for gene: EIF3M were set to
COVID-19 research v0.350 EIF3M Catherine Snow reviewed gene: EIF3M: Rating: ; Mode of pathogenicity: None; Publications: 20676407, 15919898; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.350 TLR4 Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses.
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.
COVID-19 research v0.350 TLR4 Sarah Leigh Classified gene: TLR4 as Green List (high evidence)
COVID-19 research v0.350 TLR4 Sarah Leigh Added comment: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV).
COVID-19 research v0.350 TLR4 Sarah Leigh Gene: tlr4 has been classified as Green List (High Evidence).
COVID-19 research v0.349 HDAC6 Rebecca Foulger commented on gene: HDAC6: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response (Zheng et al, 2017). HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production and infection (Hernández et al, 2019). Depletion of HDAC6 expression (in vitro) led to impaired antiviral responses against RNA viruses, but not against DNA viruses. HDAC6 knockout mice were highly susceptible to RNA virus infections compared to wildtype mice (Choi et al, 2016). Overexpression of Hdac6 enhances resistance to virus infection in embryonic stem cells and in mice (Wang et al, 2015).

Literature:
PMID: 27959772 - Zheng et al. (2017) (Review) This review highlights current data illustrating the complexity and importance of HDAC6 in viral pathogenesis.
HDAC6 has both proviral and antiviral effects. HDAC6 can inhibit infection of both RNA and DNA virus by modulating microtubule (MT) cytoskeleton and stimulating selective autophagy and restrict viral diffusion by triggering antiviral immune response. However, RNA viruses can also utilize HDAC6-mediated aggresome pathway or proinflammatory response to facilitate viral pathogenesis (Fig 1 and Table 1)
• HDAC6 triggers antiviral gene expression upon RNA virus infection (Fig 3a)
• HDAC6 interacts with Vif or A3G and competes for Vif–A3G interaction through its BUZ domain, impairs the incorporation of Vif into nascent virions and finally controls HIV-1 infectiveness (Fig 4)
• HDAC6 facilitates viral uncoating and pathogenesis (Fig 5)
Findings support exploration of a potential therapeutic role for restricting viral pathogenesis by targeting HDAC6.

PMID: 31736889: Hernández et al. (2019) - HIV Nef is a central auxiliary protein in HIV infection and pathogenesis. Results from the study indicate that HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production
• HIV-1 Nef viral protein induces HDAC6 Degradation (Enzyme degradation by recombinant HIV-1 Nef in HEK-293T cells in both endogenous and over expressed HDAC6 is shown in Fig 1)
• Mutated Nef protein Nef-PPAA did not promote HDAC6 degradation (Figure 3A, quantified in Figure 3B). This fact may indicate that this motif is involved in Nef-mediated HDAC6 interaction and/or processing, or that a conformational change in the mutated viral protein abrogates the degradative activity observed with the wt-Nef (Figures 1–3)
• Nef assures viral production and infection by targeting HDAC6, stabilizing Pr55Gag and Vif, thereby facilitating Pr55Gag location and aggregation at plasma membrane, and subsequent virus production and infection capacity (events summarized by schematic illustrations in Figure 10)

PMID: 26746851: Choi et al. (2016) - HDAC6 plays an important role in the antiviral immune response by producing IFNs and proinflammatory cytokines in responses to foreign RNA viruses.
HDAC6+/+ and HDAC6-/- mice were intravenously infected with vesicular stomatitis virus (VSV, Indiana strain). Results show that
• HDAC6-/- mice are more susceptible to VSV-Indiana infection than HDAC6+/+ mice and showed significantly decreased survival rate (Fig 1A)
• Virus titers were significantly higher and IFN-b and IL-6 production was markedly lower in HDAC6-/- mice than in HDAC6+/+ mice (Fig 1D and E)
• Role of HDAC6 in cytokine induction by poly(I:C), which is a synthetic double-stranded RNA (dsRNA): Intravenous injection of poly(I:C) caused the rapid and robust induction of IFN-b and IL-6 in HDAC6+/+ mice; however, induction of these cytokines was significantly reduced in HDAC6-/-mice (Fig 1F).
In vitro
• HDAC6 deficiency reduces the innate immune response on mouse macrophage and mouse embryonic fibroblast (Fig 3)
• HDAC6 and RIG-I transiently interact in response to RNA viral infection (Fig 5A and B) and HDAC6 regulates the binding of RIG-I to 50 pppdsRNA by deacetylating RIG-I (Fig 5G)

PMID: 25482409 Wang et al. (2015) - This is another study that provides a proof of principle of antivirus function by Hdac6 in vivo. HDAC6 overexpression significantly enhances resistance to avian H5N1 virus infection and extends the survival rate in Hdac6tg mice (transgenic) (Fig 2). Also, ES cells overexpressing Hdac6 displayed resistance to infection by adenovirus at high titers (Fig 1).
COVID-19 research v0.349 DAG1 Rebecca Foulger commented on gene: DAG1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007).

PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection.

PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs.

PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses.
Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands.

PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function.
Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis.

PMID 15857984: Kunz et al. (2005)
Show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range.
Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells.
LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding.
LCMV uses the same domains of α-DG for binding that are used in LFV binding.
Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates.
COVID-19 research v0.349 BECN1 Rebecca Foulger commented on gene: BECN1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): BECN1 encodes the beclin1 protein which is an established regulator of the autophagic pathway. Autophagy is a key mechanism against invading bacteria, parasites, and viruses in innate immune cells including monocytes/macrophages, dendritic cells and neutrophils (reviewed in Tao et al. 2020). Viral proteins such as HIV-1 Nef, ICP34.5 of HSV-1 and M11 of MHV-68 have been shown to interact with Beclin-1 and block the late stage of autophagy, thereby protecting viral particles from degradation (Kyei et al 2009; Orvedahl et al. (2007); Ku et al. (2008)

PMID:32265919 Tao et al. 2020 (review) - Autophagy is a key mechanism against invading bacteria, parasites, and viruses in innate immune cells including monocytes/macrophages, dendritic cells (conventional dendritic cells-cDCs and plasmacytoid dendritic cells-pDCs) and neutrophils. BECN1 encodes beclin1 protein which is an established regulator of the autophagic pathway. Viral proteins may target BECN1 to inhibit autophagy.

PMID: 19635843 Kyei et al. (2009) - A series of experiments showed that the Nef protein of HIV inhibits the autophagic maturation pathway (fig 5). Macrophages transfected with Nef-GFP showed colocalization of Nef with Beclin-1 and the two proteins were shown to physically interact in immunoprecipitation experiments (Fig6).

PMID: 18248095 Ku et al. (2008) - In NIH3T3 cell culture studies, the M11, a viral BCL-2 of murine gamma herpesvirus 68 was shown to bind Beclin-1 and to inhibit to inhibit Beclin-1 mediated autophagy (Fig 4).

PMID: 18005679 Orvedahl et al. (2007) - The authors used coimmunoprecipitation experiments in both HEK293 cells and embryonic stem cells to show that the neurovirulence protein of Herpes simplex virus (HSV)-1, ICP34.5, binds to the C terminus of BECN1 (Fig 2). In MCF7 stably expressing BECN1cells, transfection of the ICP34.5 inhibited autophagy (Fig 2). Mutant HSV-1 lacking the ICP34.5 BECN1-binding domain failed to inhibit autophagy in primary sympathetic neurons (Fig 5A) and had impaired ability to cause lethal encephalitis in mice (Fig 6) .
COVID-19 research v0.349 CXCL8 Rebecca Foulger commented on gene: CXCL8: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor):

• CXCL8 is a proinflammatory chemokine that plays a role in inflammatory response and immune cell trafficking
• Multiple studies show IL-8 levels were shown to be elevated in plasma of patients with COVID-19, SARS-CoV, or MERS-CoV compared to controls. These include a number of recent COVID-19 studies (Coperchini et al. 2020).
• Higher levels were detected in more severe cases (Gong et al. 2020; Qin et al. 2020; Yan et al. 2020), although one study shows the levels are within the normal range (Qin et al. 2020)
• Gong et al. (2020) suggest that IL-8 might be a therapeutic target COVID-19

Literature:
PMID 32446778; Coperchini et al. (2020)
• Review article describing the involvement of chemokine/chemokine-receptor system in COVID-19
• Discusses the concept of cytokine storm where the immune system is ‘attacking’ the body resulting in acute respiratory distress syndrome.
• Multiple studies are mentioned that show high levels of CXCL8 in the plasma and broncho-alveolar fluid in patients with acute respiratory distress syndrome. Reference a paper that notes that pre-treatment with an anti-CXCL8 antibody prevented acute lung injury that generally develops.
• In vivo studies showed elevated CXCL8 in patients with SARS-CoV.
• In vitro studies where peripheral blood mononuclear cells from healthy donor inoculated with SARS-CoV showed enhancement in the expression of CXCL8
• Similarly, CXCL8 was upregulated in cells lysates when with MERS-CoV infection of polarized airway epithelial cells (higher expression than SARS-CoV).
• Higher plasma levels of CXCL8 in patients with COVID-19 compared to healthy controls; however, transcription of CSCL8 was not upregulated

MedRxiv; Gong et al. (2020)
• Evaluated disease severity in a total of 100 patients with COVID-19 pneumonia
• CXCL8 (IL-8 in this paper) was detected in these patients and IL-8 levels were shown to be associated with disease severity (P<0.001); significant differences were noted between critical and severe patients or critical and mild groups (Tables 2 and 3)
• Suggest that IL-8 might be a therapeutic target COVID-19

PMID 32161940; Qin et al. (2020)
• Retrospective study of 452 patients with COVID-19; severity of COVID-19 defined according to the Fifth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance
• Clinical and laboratory data were collected
• A majority of the severe cases (n=286) had elevated levels of IL-8 (18.4 pg/mL vs 13.7 pg/mL, respectively; p<0.001) compared to the nonsevere cases (n=166), although they were all in the normal (0-62.0 pg/mL) (Table 2)

MedRxiv; Yan et al. (2020)
• Identified 25 genes that showed highly conserved kinetics in COVID-19 patients
• Figure 3F shows expression of CXCL8 and plasma levels of IL-8 from four individuals with COVID-19 compared to four healthy controls was higher in patients especially in the severe stage (p<0.001)

PMID 15585888; Chang et al. (2004)
• Introduction has a summary of previously published papers and notes that high serum levels of IL-8 were detected during acute phase and associated with lung lesions in patients with SARS in one study. Another study suggests use of corticosteroids in reducing pulmonary inflammation due to IL-8.

• Chang et al. (2004) used transient transfection of the SARS-CoV S protein-encoding plasmid on the IL-8 promoter. Measure of IL-8 release in lung cells showed an upregulation of IL-8 release. In addition, a specific region of the S protein was identified as a potentially important region for inducing IL-8 release.

There are additional case-control studies suggesting possible association of polymorphisms in CXCL8 and acute bronchiolitis susceptibility (Pinto et al. 2017; PMID 27890033), asthma (Charrad et al. 2017; PMID 28993876), or human papillomavirus infection (weaker evidence; Junior et al. 2016; PMID 27783717).
COVID-19 research v0.349 TLR4 Sarah Leigh reviewed gene: TLR4: Rating: ; Mode of pathogenicity: None; Publications: 11062499, 17579031, 17709532; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.349 VPS11 Rebecca Foulger commented on gene: VPS11: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The VPS11 gene encodes a protein which is part of the homotypic fusion and vacuole protein-sorting (HOPS) complex that mediates fusion of endosome and lysosomes; VPS11 is involved in late-stage endosome to lysosome maturation. In HAP1 cells mutagenized with a retroviral gene-trap vector, mutations in VSP11 were enriched in Ebola virus-resistant cells. In addition, VPS11-deficient cells showed resistance to Ebola and Marburg virus compared to controls. Escape of the Ebola virus to the cytoplasm was blocked in VPS11-deficient cells (Carette et al. 2011). In HeLa cells RNAi downregulation of VPS11 showed decreased relative percentage infection with mouse hepatitis coronavirus (MHV) and feline infectious peritonitis virus, with a larger effect for MHV (Burkard et al. 2014). Similarly, in HEK293 cells, luciferase activity of Ebola virus and SARS-CoV-S were reduced in siRNA downregulated VPS11 cells (Zhou et al. 2016).

PMID 21866103; Carette et al. (2011) - Used retroviral gene-trap vector to mutagenize HAP1 cells. Identified genes enriched for mutations in vesicular stomatitis virus bearing the EboV glycoprotein (rVSV-GP-EboV)-resistant cells. Enriched for mutations in VPS11 as well as other subunits of the HOPS complex (six subunits including VPS11), which mediates fusion of endosome and lysosomes; VPS11 is involved in late-stage endosome to lysosome maturation. In addition, VPS11-deficient cells (using gene-trap insertions) showed resistance to infection with Marburg virus or Ebola virus (Figures 1C and Figure S4C) compared to controls. Ebola virus escape to the cytoplasm is blocked in VPS11-deficient cells compared to WT (Figure 3D)

PMID 25375324; Burkard et al. (2014) - Evaluated entry of mouse hepatitis coronavirus (MHV) in HeLa cells with GFP-expressing MHV RNAi mediated downregulation of VPS11 (using three different siRNAs) showed the percentage of relative infection was reduced compared to negative siRNA controls (Figure 1C). Luciferase expressing feline infectious peritonitis virus (FIPV) was also evaluated in HeLa cells and RNAi mediated downregulation of VPS11 showed reduced relative infection for two of three siRNAs compared to negative siRNA controls (Figure 10)

PMID 26953343; Zhou et al. (2016) - Study to evaluate effects of antibiotics on proteins involved in virus entry. SiRNA-mediated knockdown of VSP11 expression showed decreased relative luciferase activity in HEK293 cells infected with Ebola virus or SARS-CoV-S, but not with vesicular stomatitis virus. In addition, treatment with the glycopeptide antibiotic teicoplanin did not show an effect on the HOPS complex
COVID-19 research v0.349 RNASEL Rebecca Foulger commented on gene: RNASEL: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): RNASEL, also known as 2-5A-dependent RNase is a component of the interferon-regulated 2-5A system that functions in the antiviral interferon pathway. Treatment of cells with interferon results in enhanced levels of both 2-5A-dependent RNase and a group of synthetases that produce 5-prime-triphosphorylated, 2-prime,5-prime-oligoadenylates (2-5A) from ATP. The role of the 2-5A system in the control of viral and cellular growth suggests that defects in the 2-5A-dependent RNase gene could result in reduced immunity to virus infections and cancer (Hassel et al., 1993). Several studies aiming to identify a genetic association between RNASEL and viral susceptibility have failed to identified statistically significant SNPs (Yakub et al. 2005; Arredondo et al. 2012). However, there is sufficient experimental evidence, including a mouse model and in-vitro studies that RNASEL is an important contributor in host defence against several viruses (Gusho et al. 2016 (review); Zhou et al. 1997; Panda et al. 2019).

PMID 27595182: Gusho et al. 2016 (review) - RNase L is a unique IFN-regulated endoribonuclease that serves as an important mediator of antiviral innate immunity with possible roles in antibacterial defense and prostate cancer. It is controlled by IFN-inducible oligo-adenylate synthetases (OASs) and double-stranded RNAs (dsRNAs). OAS-RNase L (Fig. 1) pathway, discovered in the mid-1970s, was one of the first IFN-dependent antiviral pathways to be characterized. OASs are IFN-I/-III-inducible genes that are expressed at very low basal levels in many cell types. OASs1-3 act as pathogen recognition receptors that sense dsRNAs and activate the synthesis of 5’-phosphorylated 2’-5’ linked oligoadenylates from ATP (2-5A). 2-5A acts as a second messenger and binds monomeric RNase L, and activates its dimer formation. Active RNase L cleaves cellular and viral RNAs within single-stranded regions. RNA degradation directly and indirectly activates subsequent events, including the elimination of viral genomes, inhibition of cellular and viral protein synthesis; and activation of several cellular signaling pathways, including those involved in autophagy, apoptosis, senescence, IFN-b production, and NLRP3-inflammasome activation as part of its antiviral mechanism (references provided). Authors state that many viruses have evolved or acquired strategies that antagonize the OAS-RNase L pathway to evade antiviral innate immunity. Some, such as Influenza A (IAV), HSV and Vaccinia virus act through an RNA-binding domain which binds to and sequesters dsRNA, the activator of OAS. Others bind directly to monomeric RNase L preventing it from activation by dimerization. Some coronaviruses (MERS-CoV and MHV) are described to act through their ns-domains with 2’-5’ PDE activity that degrades 2-5A and thus prevent activation of RNase L.

Some additional evidence of interest:
-OAS3 was shown to exert antiviral activity against Dengue virus in an RNase L-dependent manner, indicating that OAS3 synthesizes active 2-5A in sufficient amounts for RNase L activation
-RNase L activation by dsRNA signaling or viral infection contributes to IFN-b production, indicating its important role in innate immunity. The ribonuclease function of RNase L is essential for its effect on IFN-b production
-Moreover, mice deficient in RNase L had several-fold reduced levels of IFN-b induction after infection with RNA viruses (EMCV and Sendai virus)
-Stable expression of wild-type human full-length RNase L, but not ribonuclease dead mutant (R667A), activates IL-1b and caspase 1 secretion in RNase L-deficient THP1 cells after virus infection or 2-5A transfection

PMID 9351818: Zhou et al. (1997) RNASEL Mouse model
To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon was impaired in RNaseL–/– mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. Authors showed that EMCV replicates more efficiently in cells lacking RNase L than in wild type cells, even after interferon treatment, although the effect is relatively small. Next, authors determined that survival of RNaseL-/- mice after EMCV infection was significantly reduced both in presence and absence of IF (Fig 3). Enlarged thymus and reduced level of apoptosis in thymus and spleen were also found (Fig 4-5).

PMID 31156620 Panda et al (2019)
Interferon regulatory factor-1 (IRF1) regulates expression of RNaseL and knockdown of RNaseL in BEAS-2B cells resulted in significantly increased VSV infection rates. (Fig.6)

PMID 22356654 Arredondo et al. 2012
Authors studied allelic variants in RNASEL gene at codon 462 (R462Q, rs486907) for susceptibility to viral infection, prostate cancer and chronic fatigue syndrome. The allelic distribution at codon 462 was 139 (33.9%), 204 (49.8%), and 67 (16.3%) for RR, RQ, and QQ, respectively, in 410 individuals in Spain. There were no significant differences comparing 105 blood donors and 71 patients with HIV-1 infection, 27 with chronic hepatitis C, 67 with prostate cancer, and 107 with chronic fatigue syndrome. In contrast, two-thirds of 18 patients with HTLV-1 infection and 15 with chronic hepatitis B harbored RR (Table 1). Thus, polymorphisms at the RNASEL gene do not seem to influence the susceptibility to common viral infections or conditions potentially of viral etiology. They conclude that the role in influencing the susceptibility to HTLV-1 or HBV chronic infection warrants further examination in larger patient populations.
COVID-19 research v0.349 PVR Rebecca Foulger commented on gene: PVR: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): PVR, or CD155, belongs to a large family of immunoglobulin (Ig)-like molecules called nectins and nectin-like proteins, which mediate cell-cell adhesion, cell migration, and cell polarization through interaction with other nectins. It is both a viral receptor and immunomodulatory protein and is involved in many biological processes. PVR serves as the entry receptor for poliovirus and thereby is responsible for human susceptibility to poliovirus infection. Susceptibility to poliovirus is a function of the presence or absence of the cellular receptor to which the virus binds as the first step in poliovirus replication. Mendelsohn et al. (1986) succeeded in transforming a human poliovirus receptor gene into mouse L cells, which are ordinarily resistant to poliovirus infection because they do not bear a poliovirus receptor. Monoclonal antibody directed against the HeLa cell poliovirus receptor site was used in rosette assays to identify poliovirus-sensitive transformants. Evidence for PVR as a Viral Receptor, regulator of immune function and its role in cancer is described in Bowers et al (2017). CD155-deficient mice develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response (Maier et al, 2007)

Literature:
PMID: 28870470 - Bowers et al, 2017 (Review) - PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. PVR undergoes alternative splicing, generating 4 unique splice forms. Protein isoforms and interactions with Poliovirus are summarized in Table 1. In addition to its role as a receptor for the human poliovirus, several native biological functions have also been uncovered. PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. Through its interactions with CD226 and TIGIT, transmembrane proteins found on leukocytes, PVR is a key regulator of the cell-mediated immune response. In this review more evidence is available for PVR as a Viral Receptor and PVR as a regulator of immune function

PMID: 25113908 - Bolduan et al, 2014 - NL4-3 Vpu protein from HIV downregulates the activating NK cell receptor CD155 from the cell surface by the conserved alanine residues Ala-10, Ala-14 and Ala-18 of its TM domain to evade NK cell mediated immune response against HIV-1 infected cells (Hela cells)
PMID: 19815499 - Stanietsky et al, 2009 - TIGIT (a protein expressed by all human NK cells) binds PVR and PVRL2 but not PVRL3 and inhibits NK cytotoxicity directly through its ITIM.

PMID: 12943679 - Baury et al, 2003 -As the extracellular domains of the sPVR (soluble PVR) isoforms are identical to the extracellular domain of transmembrane PVR, they can compete with transmembrane PVR for the canyon-like receptor binding site of poliovirus. When sPVR is overexpressed in poliovirus susceptible HeLa cells, it significantly reduces viral entry and viral infectivity

PMID: 17621371 - Maier et al, 2007 - In this study, Maier et al explore the expression profile of CD155 on murine hematopoietic cells utilizing newly generated mAb. They report on the establishment and immunological analysis of mice deficient in CD155. CD155-deficient mice (knock out) develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response. Whereas systemic challenges revealed no differences, orally administered antigen evoked less efficient IgG and IgA antibody responses (Figure 7) despite of normal IgM titers when compared to wild-type mice. Therefore, CD155 may assist in an efficient humoral immune response generated within the intestinal immune system.

PMID: 28800489 - Lin et al, 2017 - Amino acid changes in the C’C”D region in poliovirus receptor domain 1 disrupt poliovirus binding. We substituted this region of Pvr into the corresponding region of a murine homolog, nectin-2. The chimeric receptor, nectin-2Pvr(c'c"d), rendered transformed L cells susceptible to infection with poliovirus P1/Mahoney, but not with polioviruses P2/ Lansing and P3/Leon, due to lack of binding.

PMID: 2597248 - Kanemaru et al, 2015 - Mice genetically deficient in CD155 or treated with anti-CD155 Ab exhibited attenuated Th1-type contact hypersensitivity. Thus, CD155 plays an important regulatory role in helper T cell differentiation and allergic diseases.
COVID-19 research v0.349 EGFR Catherine Snow Publications for gene: EGFR were set to
COVID-19 research v0.348 EGFR Catherine Snow reviewed gene: EGFR: Rating: ; Mode of pathogenicity: None; Publications: 28390872, 31616667, 8523580, 28404843, 20844577; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.348 PTX3 Rebecca Foulger commented on gene: PTX3: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Pentraxins are a superfamily of conserved humoral mediators of innate immunity. PTX3, the prototypic long pentraxin, is a soluble pattern recognition molecule produced by several cell types in response to primary pro-inflammatory signals and microbial recognition. It is involved in the initiation of protective responses against select pathogens, acting as an important mediator of innate immunity against pathogens of fungal, bacterial and viral origin, and as a regulator of inflammation, by modulating complement activation and cell extravasation, and facilitating pathogen recognition by myeloid cells. It is an established biomarker in sepsis, with PTX3 plasma levels associated with severity of the condition, patient survival, and response to therapy.

PTX3 has been characterized as a biomarker of severity and outcomes in different infections caused by bacteria, fungi or viruses. Patients with pulmonary aspergillosis, tuberculosis, dengue virus infection, meningococcal disease leptospirosis and shigellosis have increased PTX3 plasma levels that correlate with disease severity and could act as predictor of unfavourable outcomes (PMID 31031772: Porte et al. 2019). Several studies using Ptx3-deficient mice showed an increased susceptibility to fungal, bacterial and viral pathogens (Porte et al. 2019). In contrast, a study in PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication (Foo et al. 2015). PTX3 administration has shown to be protective also against infections with Influenza virus, murine cytomegalovirus, Neisseria meningitidis, and P. aeruginosa in neonates and during chronic infections by reducing viral load and inflammatory pathology. (PMID 31031772: Porte et al. 2019, PMD 18292565: Reading et al. 2008).

PMID: 25695775: Foo et al. (2015) - Found that pentraxin 3 (PTX3) was highly expressed in chikungunya virus (CHIKV) and Ross River virus (RRV) patients during acute disease. Overt expression of PTX3 in CHIKV patients was associated with increased viral load and disease severity. PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication. Furthermore, binding of the N-terminal domain of PTX3 to RRV facilitated viral entry and replication.

PMID: 18292565 - Reading et al. (2008) - Identified the long pentraxin PTX3 as a potent innate inhibitor of influenza viruses both in vitro and in vivo. Human and murine PTX3 bound to influenza virus and mediated a range of antiviral activities, including inhibition of hemagglutination, neutralization of virus infectivity and inhibition of viral neuraminidase. Antiviral activity was associated with binding of the viral hemagglutinin glycoprotein to sialylated ligands present on PTX3. Using a mouse model found PTX3 to be rapidly induced following influenza infection and that PTX3-/- mice were more susceptible than wild-type mice to infection by PTX3-sensitive virus strains. Therapeutic treatment of mice with human PTX3 promoted survival and reduced viral load in the lungs following infection with PTX3-sensitive, but not PTX3-resistant, influenza viruses.

PMID 19968561: Bottazzi et al. (2010) (Review) - PTX3 binds to human and murine cytomegalovirus and influenza virus type A (IVA). The interaction between PTX3 and IVA occurs through binding of sialylated ligands on PTX3 to the viral hemagglutinin and results in neutralization of virus infectivity in vitro. Consistently, desialylated PTX3 does not bind IVA and does not neutralize virus infectivity.
COVID-19 research v0.348 NPC1 Rebecca Foulger commented on gene: NPC1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): NPC1 encodes a polytopic protein that resides in the limiting membrane of late endosomes and lysosomes (LE/LY) and mediates distribution of lipoprotein-derived cholesterol in cells (Cote et al. (2011). NPC1 expression is critical for filovirus infection (EboV and MarV) and the mechanism of infection is not dependent on NPC1 cholesterol transport activity (Carette et al. 2011). Structural studies demonstrate that the C-domain of NPC1 binds to the primed EBOV glycoprotein (Wang et al. 2016; Gong et al. 2016).

PMID 21866103: Carette et al. (2011)
Genome-wide haploid genetic screen was performed in primary fibroblasts derived from human Niemann-Pick type C1 disease patients to identify host factors required for Filovirus infection. These cells are resistant to infection by EboV and MarV but remain fully susceptible to other unrelated viruses (Figure 2A, B). Resistance of NPC1-deficient cells was not caused by cholesterol transport defects (Fig S8). Infection in these cells was restored by expression of wild type NPC1 (Figure 2C). Similar results were observed in NPC1-null Chinese hamster ovary (CHO) cells, with loss of NPC1 conferring complete resistance to viral infection (Figure S6D) that was reversed by expression of human NPC1 (Figure S6E). Electron micrographs of NPC1 mutant cells infected with rVSV-GP-EboV indicate that NPC1 is required in downstream process in filovirus entry leading to viral membrane fusion and escape from the lysosomal compartment. Knockdown of NPC1 in HUVEC diminished infection by filoviruses (Figure 4D and S18) suggesting that NPC1 is critical for authentic filovirus infection. Furthermore, NPC1+/+ mice rapidly succumb to infection with either filovirus while NPC1−/+ mice were largely protected (Figure 4E).

PMID 2186610: Cote et al. (2011)
HeLa cells treated with benzylpiperazine adamantane diamide-derived compounds (3.0 and 3.47) developed cytoplasmic vacuoles indicating that that they target one or more proteins involved in regulation of cholesterol uptake in cells. CHO cells lacking NPC1 were completely resistant to infection by this virus and infection of these cells was fully restored when NPC1 was expressed. NPC1 expression but not NPC1-dependent cholesterol transport activity is essential for EboV infection (Fig 2c). 3.0-derived compounds inhibit EboV infection by interfering with binding of cleaved glycoprotein to NPC1 (Fig 4).

PMID 26771495: Wang et al. (2016)
The crystal structure of the primed glycoprotein (GPcl) of Ebola virus and domain C of NPC1 (NPC1-C) demonstrates that the NPC1-C binds to the primed EBOV GP (Fig 1, 3). Further, it suggests that a membrane-fusion-priming conformational change occurs in GPcl or the binding of GPcl, and this is a unique feature for all the filoviruses. NPC1-interacting compound 3.47 competitively blocks the primed GP binding to the membrane probably binds to the two protruding loops of NPC1-C. Compound U18666A binds to a different site on NPC1 causing endosomal calcium depletion. Furthermore, peptide inhibitors or small molecules, which can easily penetrate the cell membrane and reach the primed GP in the late endosomes could also act as potential therapeutic agents.

PMID 27238017: Gong et al. (2016)
Full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV was determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three lumenal domains, A (NTD), C, and I. TMs 2–13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3–7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. EBOV-GPcl binds to NPC1 through the domain C.
COVID-19 research v0.348 NECTIN1 Rebecca Foulger commented on gene: NECTIN1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Amino acid substitutions in nectin-1 showed impaired entry of Herpes simplex virus (HSV) into CHO-K1 cells (PMID:1175687;12072525). Nectin-1 knockout mice inoculated with HSV in the hippocampus demonstrated that nectin-1 is necessary for neurologic disease caused by HSV (PMID:19805039).

PMID 11756979 - Struyf et al. (2002) - Searched for polymorphisms in HVEM, nectin-1, and nectin-2 via sequencing in individuals shown to immune seronegative for herpes simplex virus (HSV). These individuals showed T cell responses to HSV antigens and did not have anti-HSV antibodies detected in their serum. There were three individuals that were immune seronegative, three with no signs of cellular or humoral immunity, and three with frequent reactivations of HSV who had antibody and T cell responses to HSV. One individual in the study (true seronegative as demonstrated by negative testing for HSV-1 and HSV-2 and no HSV-specific T cell immunity) was identified to have a variant in nectin-1 (c.752G>A, p.Arg199Gln) in addition to one missense variant in HVEM (table 2). This variant was screened for 644 healthy White individuals and 17 were shown to be heterozygous for the p.Arg199Gln variant and one individual had a different missense variant at the same residue. The p.Arg199Gln variant occurs in the first constant-like domain for the protein. A different domain, the N-terminal variable-like domain, has previously been shown as important for virus entry into the cell.

PMID 12072525 - Martinez and Spear (2002) - Investigated whether residues 75-77 and 85 of nectin-1 (homologous to regions A and B of nectin-2) are necessary for HSV-1 entry into CHO-K1 cells (which are resistant to the entry of alphaherpesviruses unless they are created to express a gD receptor). When there were mutants involving both residues 77 and 85, there was severely diminished ability of HSV-1 or HSV-2 to enter the cell and was unable to find to soluble forms of HSV-1 and HSV-2 (table 1; fig. 3). Note that these mutants allowed entry of PRV and BHV-1.

PMID 19805039 - Kopp et al. (2009) - Nectin-1 knockout (KO) mice were inoculated intracranially and into the hippocampus with herpes simplex virus (HSV) and infection of neurons compared to HVEM KO mice, HVEM/nectin-1 KO mice, and controls. Nectin-1 KO mice were resistant to disease, as were the double KO mice at doses of the virus up to 100x needed to cause disease as compared to the wildtype and HVEM KO mice (Fig. 1). Nectin-1 is necessary for neurologic disease caused by HSV. Viral antigen was not detected in brain sections from double KO mice, but could be detected for nectin-1 KO mice (limited regions), HVEM-KO mice and wildtype (more widespread) (Fig. 2A). HSV was shown to be located to the ventricular surfaces in nectin-1 KO mice and confirmed as non-parenchymal cells (Fig. 2B).
COVID-19 research v0.348 MIR155 Rebecca Foulger commented on gene: MIR155: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): MIR155 (also referred to as BIC) is an endogenous noncoding RNA involved in regulation of the immune response, in particular T-cell differentiation, and in regulation of innate immunity (PMID: 32233818; 217121651;1746328969;20852130). This miRNA has been associated with various virus infections (PMID: 32233818;28139244;23686237;26072128). miR-155-5p expression has been shown to be induced in mice infected with influenza A virus (PMID: 32308197 - in this study, lung injury by ARDS was attenuated by deletion of miR-155, making this miRNA a potential therapeutic target in the context of COVID-19). Through single cell and bulk RNA profiling of SARS-CoV-2 and SARS-CoV infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), Emanuel et al. (2020) (bioRxiv preprint doi: https://doi.org/10.1101/2020.05.05.079194) demonstrated strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon viral infection with both viruses. Both viruses triggered a 16-fold upregulation of one form of miR-155 and a 3-fold upregulation of another.

A role for MIR155 in viral susceptibility for a range of viruses and the immune response has also been demonstrated in a series of mouse models:

PMID 23601686: In Mir155 -/- mice, Dudda et al. (2013) observed severely reduced accumulation of Cd8-positive T cells during acute and chronic viral infections with impaired control of viral replication. Lack of Mir155 led to an accumulation of Socs1 resulting in defective cytokine signaling through Stat5. Dudda et al. also concluded that MIR155 and its target, SOCS1, are key regulators of CD8-positive T cells.

PMID 23275599: Lind et al. (2013) found that mice lacking Mir155 had impaired Cd8 positive T-cell responses to infections with lymphocytic choriomeningitis virus and the intracellular bacteria Listeria monocytogenes and concluded that MIR155 is required for acute CD8-positive T-cell responses and proposed that targeting MIR155 may be useful in modulating immune responses.

PMID 24516198: Bhela et al. (2014) – 75 to 80% of MIR155 null mice infected ocularly with herpes simplex virus (HSV)-1 developed herpes simplex encephalitis with elevated viral titers in brain, but not in cornea. Immunohistochemical and flow cytometric analyses in Mir155-null mice showed diminished Cd8-positive T-cell numbers, functionality, and homing capacity. Adoptive transfer of HSV-1-immune Cd8-positive T cells to Mir155-null mice 24 hours after infection provided protection from HSE. The authors concluded that MIR155 deficiency results in enhanced susceptibility of the nervous system to HSV-1 infection.
COVID-19 research v0.348 KLF2 Rebecca Foulger commented on gene: KLF2: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): KLF2 is a member of the Kruppel-like factor (KLF) family of zinc finger transcription factors that function in cell differentiation, quiescence, and homeostasis. It also plays a regulatory role in inflammation-related pathways (Jha and Das 2017). Richardson et al. (2012) showed that KLF2 acts as a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to infection with CCR5-dependent HIV-1 strains. Huang et al. (2017) showed through both network analyses and experimental results that KLF2 plays a central role in regulating many genes associated with acute respiratory distress syndrome (ARDS) identified by GWAS and that overexpression of KLF2 in vivo in mice could mitigate lung injury and expression of inflammatory genes, including that induced by influenza A virus.

PMID 17141159: Lee et al. (2006) - KLF2 deficient mice die in prenatal stage due to vascular defects, highlighting its crucial role in embryonic development. Lethal high-output heart failure, as found in the KO mice, was also observed in zebrafish embryos after morpholino inhibition of the Klf2 ortholog klf2a. CD4+ T cells from KLF2-deficient mice expressed multiple inflammatory chemokine receptors, suggesting that loss of KLF2 leads to redirection of naïve T cells to nonlymphoid sites (Sebzda et al., 2008).

PMID 19592277: Weinreich et al. (2009) - Demonstrated upregulation of the chemokine receptor CXCR3 on KLF2-deficient T cells (Fig. 1). KLF2-deficient T cells also overproduced IL-4 (Fig. 5).

PMID 22988032: Richardson et al. (2012) - Tested whether the abundance of KLF2 after T cell activation regulates CCR5 expression and, thus, susceptibility of a T cell to CCR5-dependent HIV-1 strains (R5). Introduced small interfering RNA targeting KLF2 expression and demonstrated that reduced KLF2 expression also resulted in less CCR5 (Fig. 3). Introduction of KLF2 under control of a heterologous promoter could restore CCR5 expression and R5 susceptibility to CD3/28 costimulated T cells and some transformed cell lines (Fig. 5, 6). KLF2 is a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to R5 infection.

PMID 29125549: (review) Jha and Das (2017) - KLF2 also plays a critical regulatory role in various inflammatory diseases and their pathogenesis.

PMID 27855271: Huang et al. (2017) - Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow to examine the role of the gene in endothelial barrier disruption and cytokine storm in experimental lung injury. Pulmonary Klf2 was down-regulated by inflammation induced by influenza A/WSN/H1N1 virus (H1N1) infection, LPS administration, or LPS administration followed by high tidal volume ventilation in vivo (Fig. 1). It was also down-regulated by pathologic stretch and inflammatory stimuli (Fig. 2). Knockdown of endogenous KLF2 reduces Rac1 activation in human pulmonary microvascular cells, whereas adenovirus-mediated transduction with KLF2 promoted Rac1 activation (Fig. 3). Computational predictive pathway analysis suggested that KLF2 acts to regulate ARDS-associated GWAS genes, including ACE, NAD(P)H, NQO1, SERPINE1/PAI-1, TNF, and NF-kappaB. Expression studies in mice confirmed this regulatory role (Fig. 8). Overexpression of KLF2 in vivo in mice could also mitigate lung injury and expression of inflammatory genes (Fig. 7).
COVID-19 research v0.348 IRF2 Rebecca Foulger commented on gene: IRF2: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): IRF2 encodes interferon regulatory factor 2, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF2 is an antiviral IFN-stimulated gene (ISG) which negatively regulates IFN signalling. (Lukele et al. 2019 -review). In both cell culture and the knock out Irf2-/- mouse model, Irf2 deficiency leads to an increase in susceptibility to viral infection (Schoggins et al. 2011; Karki et al. 2012; Matsuyama et al. 1993; Grieder et al. 1999). Irf2-/- mice also show increased susceptibility to neurotrophic viruses, including SINV and VSV, when compared to wild type mice. The compromised development and maturation of multiple immune cell types in the Irf2−/− mice which lead to reduced B cells and virus specific IgG levels in the brains of infected mice was linked to the pathogenic phenotype (Melody et al. 2016). These data suggest IRF2 may also play an important role in the development of the immune system.

PMID: 21478870 Schoggins et al. (2011) - The authors over expressed over 380 ISGs to test their ability to inhibit the replication of viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Each gene was expressed in a lentiviral construct transfected into various cell lines. Cells were challenged with GFP expressing virus and replication was quantified by flow cytometry. IRF2 was shown to be a anti-HCV ISGs.

PMID: 22615998 Karki et al. (2012) - Karki et al. used a library of lentiviruses individually expressing more than 350 ISGs, transduced in HuH-7 cells in the presence of absence of ZAP and identified IRF2 as an enhancer of viral inhibition upon infection with SINV. In confirmatory experiments, when both ZAP and IRF2 were knocked down, viral replication was significantly increased compared to ZAP or IRF2 silencing alone, which supports the results obtained in the ISG overexpression screen and suggests that endogenous ZAP and IRF2 might interact in a synergistic manner (Fig. 5).

PMID: 10208925 Grieder et al. (1999) - Irf2−/− mice show increased susceptibility to virulent Venezuelan equine encephalitis (VEE) virus infection even after vaccination with attenuated VEE, suggesting IRF2 is required to mount a protective immune response (Grieder and Vogel, 1999)

PMID: 22113474 Gao et al. (2012) - The authors found IRF2 variants to be risk alleles for atopic dermatitis and eczema herpeticum. Eight SNPs were found to be significantly associated with reduced IFN-γ production after stimulation with herpes simplex virus. In the cohort, none of the SNPs showed association with HSV positivity.

PMID: 27899441 Melody et al. (2016) - Fig 1. Lrf2 mice show lethality upon peritoneal infection with either SINV or VSV virus (Fig 1) Irf2−/− and WT mice were challenged i.p. with SVN, a neurovirulent but noninvasive strain, which normally replicates only in the periphery without lethality in mice. Approximately 70% of the Irf2−/− mice succumbed to infection with SVN, whereas all of the WT littermate control mice survived (Fig. 1 A), indicating that IRF2 deficiency confers lethal neuroinvasive properties on the normally noninvasive SVN strain. Infection with VSV led to survival of all the WT mice, whereas ∼60% of the Irf2−/− mice suffered from paralysis and succumbed to infection. Staining using Evans blue showed that the integrity of the blood brain barrier is maintained during the infection(fig 2). The survival of lrf-/- mice treated with IFNAR-1 blocking antibody at 2dpi was similar to treatment with a control antibody, suggesting that peripheral elevation of type I IFN signalling is not responsible for the susceptibility (fig 3). Development and maturation of multiple immune cell subsets are compromised in Irf2−/− mice at baseline and upon SVN infection. B cells and virus-specific IgG level are significantly reduced in Irf2 -/- mouse brains, periorbital injection of naïve Bcells from WT mice 1day before infection did not affect lethality in the lrf2-/1 mice.
COVID-19 research v0.348 IFNE Rebecca Foulger commented on gene: IFNE: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): IFNE encodes IFNε, a type I interferon which is constitutively expressed within the epithelial cells of the female reproductive tract (FRT) and plays a role in protection against viral and bacterial infections of the FRT (Marks et al. 2019 review). Ifnε-deficient mice have increased susceptibility to infection of the FRT by Herpes Simplex Virus (HSV)-2 as well as bacterial Chlamydia muridarum(Fung et al. 2013). Ifnε activity has also been shown to reduce the infectivity of HIV through the induction of HIV restriction factors which act to inhibit different stages of the virus replication cycle (Garcia-Minambres et al. 2017; Stifter et al. 2018).

PMID: 31734130: Marks et al (2019) Review - IFNE encodes IFNε, a type I interferon which is constitutively expressed within the epithelial cells of the female reproductive tract. Ifnε expression fluctuates during pregnancy and across stages of the reproductive cycle in humans and mice. Unlike other type I interferons IFNε is not regulated by PRR pathways.

PMID: 23449591; Fung et al. 2013 - Ifnε-deficient mice had increased susceptibility to infection of the FRT by common sexually transmitted infections (STIs) Herpes Simplex Virus (HSV)-2 (fig 3) as measured by clinical scores of disease day 6 post infection. The Ifnε-deficient mice also showed high viral titres in the spinal cord and brain stem 7 days post infection, consistent with increase replication of the virus and/or retrograde transport of the virus. A similar susceptibility to infection by the bacterial Chlamydia muridarum was also observed (Fig 4).

PMID: 28045025 Garcia-Minambres et al. (2017) - Ifnε activity was shown to impair HIV infection through induction of HIV restriction factors which act to inhibit different stages of the viral replication cycle.

PMID: 29187603 Stifter et al. (2018) - Using different cell lines and reporter assays to measure interferon type I stimulation, the authors showed that recombinant murine Ifnε inhibited HIV infection in the sup-T1 cell line and in primary peripheral blood lymphocytes and furthermore induced a number of HIV restriction factors.
COVID-19 research v0.348 FOLR1 Rebecca Foulger commented on gene: FOLR1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The FOLR1 gene encodes the folate receptor alpha (FR alpha), a glycosyl-phosphatidylinositol-linked (GPI-linked) protein that binds folic acid for transport into the cytoplasm. Chan et al. (2001) used genetic complementation to identify FR-alpha as a cofactor for cellular entry of pseudo Marburg (MBG) virus and EBO-Z pseudotype into otherwise non permissive cells. Further experiments showed FR alpha specifically binds glycoproteins of these viruses to mediate syncytia (Chan et al. 2001).

PMID 11461707; Chan et al. (2001) - A complementation screen identified FR alpha as a cofactor for cellular entry of pseudo Marburg (MBG) virus into otherwise non permissive Jurkat-EctR cells (fig 1). FACs analysis showed FR alpha was present on the cell surface of other cell lines permissive for MBG infectivity (Hela cells, Vero E6, human and dog osteosarcoma cells (fig 2). FR alpha specific antagonists inhibited MBG entry (Fig 4) phospholipase C (PLC) cleaves the FR alpha receptor, cells pretreated with PLC showed decreased infectivity. When 293T cells overexpressing MBF GP were co-cultured with cells overexpressing FR alpha syncytia formation was observed, indicating that this type of membrane fusion is also mediated by FRalpha (fig 5). A similar set of experiments showed that FR alpha is also a cofactor for cellular entry of EBO-Z pseudo viruses.

Yang et al. (2019) preprint: https://doi.org/10.1101/618306 - Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, transport multiple virions en bloc via infectious extracellular vesicles secreted from host cells. Yang et al. show that in these microvesicles less than 10% of proteins are viral. 168 host cell proteins were identified in the MVs including involved in both caveolar-mediated and mediated endocytic virus entry pathways genes (ITGB1, B2M, FYN, CD55 {DAF}, HLA-A, FLNA, ACTB, RAC1, TFRC {CD71}, FOLR1).
COVID-19 research v0.348 DICER1 Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW).

IMMUNE SYSTEM
The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ.

VIRUSES
Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication.
Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis.
Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”).
Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested.

SARS CoV & SARS CoV-2
Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein
Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response.

Literature Review
PMID: 17181864: Bennasser and Jeang, 2006
• HIV-1 Tat Interaction With Dicer: Requirement for RNA
• Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain.

PMID: 18325616: Chen et al., 2008
• HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing

PMID: 26085159: Cui et al., 2015
• The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells

PMID: 24303839: Devasthanam et al, 2014
• This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets.

PMID: 28591694: Ding et al., 2017
• The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation

PMID: 30015086: Ding et al., 2018
• Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi).

PMID: 25176334: Foulkes et al., 2012-REVIEW
• Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms

PMID: 16554838: Galiana-Arnoux et al., 2006
• Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila.
• https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335

PMID: 21385408: Inchley et al., 2011
• Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease.

PMID: 32141569: Kannan et al., 2020
• COVID-19 (Novel Coronavirus 2019) - Recent Trends
• Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER.

PMID: 23849790: Klockow et al., 2013
• The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection

PMID: 25883138: Kurzynska-Kokorniak et al., 2015
• Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities

PMID: 24115437: Li et al, 2013
• Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs.

PMID: 27273616: Machitani et al., 2016
• Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA

PMID: 30872283: Maillard et al., 2019- REVIEW
• Reviewing DICER1 within the anti-viral RNAi pathway in mammals

PMID: 30682089: Modai et al, 2019
• HIV-1 infection increases miRNAs which inhibit Dicer

PMID: 32291557: Mu et al, 2020
• SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells

PMID: 16009718: Muljo et al., 2005
• Indicates absence of dicer results in abberant T-cell differentiation.

PMID: 17613256: Otsuka, et al 2007
• Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression

No PMID: Preprint : Pasquier and Rubichon, 2020
• SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system

PMID: 22438534: Qi et al., 2012
• Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells

PMID: 28473628: Song and Rossi, 2017
• Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW).

IMMUNE SYSTEM
The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ.

VIRUSES
Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication.
Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis.
Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”).
Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested.

SARS CoV & SARS CoV-2
Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein
Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response.

Literature Review
PMID: 17181864: Bennasser and Jeang, 2006
• HIV-1 Tat Interaction With Dicer: Requirement for RNA
• Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain.

PMID: 18325616: Chen et al., 2008
• HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing

PMID: 26085159: Cui et al., 2015
• The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells

PMID: 24303839: Devasthanam et al, 2014
• This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets.

PMID: 28591694: Ding et al., 2017
• The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation

PMID: 30015086: Ding et al., 2018
• Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi).

PMID: 25176334: Foulkes et al., 2012-REVIEW
• Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms

PMID: 16554838: Galiana-Arnoux et al., 2006
• Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila.
• https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335

PMID: 21385408: Inchley et al., 2011
• Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease.

PMID: 32141569: Kannan et al., 2020
• COVID-19 (Novel Coronavirus 2019) - Recent Trends
• Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER.

PMID: 23849790: Klockow et al., 2013
• The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection

PMID: 25883138: Kurzynska-Kokorniak et al., 2015
• Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities

PMID: 24115437: Li et al, 2013
• Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs.

PMID: 27273616: Machitani et al., 2016
• Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA

PMID: 30872283: Maillard et al., 2019- REVIEW
• Reviewing DICER1 within the anti-viral RNAi pathway in mammals

PMID: 30682089: Modai et al, 2019
• HIV-1 infection increases miRNAs which inhibit Dicer

PMID: 32291557: Mu et al, 2020
• SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells

PMID: 16009718: Muljo et al., 2005
• Indicates absence of dicer results in abberant T-cell differentiation.

PMID: 17613256: Otsuka, et al 2007
• Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression

No PMID: Preprint : Pasquier and Rubichon, 2020
• SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system

PMID: 22438534: Qi et al., 2012
• Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells

PMID: 28473628: Song and Rossi, 2017
• Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity
COVID-19 research v0.348 DICER1 Rebecca Foulger commented on gene: DICER1: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW).

IMMUNE SYSTEM
The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ.

VIRUSES
Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication.
Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis.
Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”).
Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested.

SARS CoV & SARS CoV-2
Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein
Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response.

Literature Review
PMID: 17181864: Bennasser and Jeang, 2006
• HIV-1 Tat Interaction With Dicer: Requirement for RNA
• Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain.

PMID: 18325616: Chen et al., 2008
• HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing

PMID: 26085159: Cui et al., 2015
• The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells

PMID: 24303839: Devasthanam et al, 2014
• This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets.

PMID: 28591694: Ding et al., 2017
• The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation

PMID: 30015086: Ding et al., 2018
• Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi).

PMID: 25176334: Foulkes et al., 2012-REVIEW
• Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms

PMID: 16554838: Galiana-Arnoux et al., 2006
• Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila.
• https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335

PMID: 21385408: Inchley et al., 2011
• Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease.

PMID: 32141569: Kannan et al., 2020
• COVID-19 (Novel Coronavirus 2019) - Recent Trends
• Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER.

PMID: 23849790: Klockow et al., 2013
• The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection

PMID: 25883138: Kurzynska-Kokorniak et al., 2015
• Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities

PMID: 24115437: Li et al, 2013
• Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs.

PMID: 27273616: Machitani et al., 2016
• Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA

PMID: 30872283: Maillard et al., 2019- REVIEW
• Reviewing DICER1 within the anti-viral RNAi pathway in mammals

PMID: 30682089: Modai et al, 2019
• HIV-1 infection increases miRNAs which inhibit Dicer

PMID: 32291557: Mu et al, 2020
• SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells

PMID: 16009718: Muljo et al., 2005
• Indicates absence of dicer results in abberant T-cell differentiation.

PMID: 17613256: Otsuka, et al 2007
• Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression

No PMID: Preprint : Pasquier and Rubichon, 2020
• SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system

PMID: 22438534: Qi et al., 2012
• Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells

PMID: 28473628: Song and Rossi, 2017
• Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity
COVID-19 research v0.348 CD28 Rebecca Foulger commented on gene: CD28: Evidence Summary from Illumina curation team: CD28 is a transmembrane receptor expressed on the surface of T cells and is required for the immune cell activation and proliferation of naïve and memory T cells. CD28 knockout mice have an increased susceptibility to ECTV, a host specific virus which causes mousepox. Upon infection, CD28 deficient mice showed a 40% mortality within 14 days while wild-type control mice did not show any symptoms of disease (Fang et al. 2008). In cell culture experiments, CD28 protein surface levels were found to be downregulated by HIV-1 accessory proteins Nef and Vpu (Pawlak et al. 2018). In severe cases of COVID-19 infection, immuno-dysregulation may lead to a decrease of CD28+ cytotoxic suppressor T cells (Tufan et al. 2020, review)

PMID: 29329537; Pawlak et al.(2018) - CD28 is a transmembrane receptor expressed on the surface of T cells. It is essential for immune cell activation and proliferation of naïve and memory T cell. Cell culture experiments using CD4+ Sup-T1 cells or primary CD4+ T cells and infected with VSV-G pseudotyped NL4.3 viruses showed that the HIV-1 accessory proteins Nef and Vpu modify the immune response and increase viral persistence by decreasing the cell surface levels of CD28 (fig.1).

PMID: 32299202; Tufan et al. (2020) Review. SARS-CoV-2 infection can lead to immune dysregulation through affecting the subset of T cells. In severe cases of COVID-19 infection, it was observed that the percentage of naïve helper T cells amplifies while the percentage of memory helper T cells and CD28+ cytotoxic suppressor T cells decreases.

PMID: 17114476; Fang et al. (2008) - CD28 KO mice in a mousepox-resistant B6 background infected with ECTV showed a 40% mortality 7–14 days PI (Fig. 1A) and all remaining CD28KO mice developed mousepox (Fig. 1, B and C). All control wild-type B6 mice survived the infection without any symptoms of disease. CD28 KO mice that survived past 14 days PI gradually recovered from the disease and survived indefinitely. A comparison of CD8+ T cell responses to ECTV and VACV suggests that the main reason for the susceptibility of CD28 KO mice to mousepox is a reduced response at the early stages of infection.
COVID-19 research v0.348 CCR2 Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team:
CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019).
PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4).

PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).; to: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019).

PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4).

PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).
COVID-19 research v0.348 CCR2 Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019).
PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4).

PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).; to: Evidence Summary from Illumina curation team:
CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019).
PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4).

PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).
COVID-19 research v0.348 CCR2 Rebecca Foulger changed review comment from: Identified through an OMIM search for potential viral susceptibility genes, and subsequently triaged/reviewed by Illumina curation team.; to: Identified through an OMIM search for potential viral susceptibility genes, and subsequently triaged/reviewed by Illumina curation team.
COVID-19 research v0.348 CCR2 Rebecca Foulger commented on gene: CCR2: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019).
PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4).

PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).
COVID-19 research v0.348 DSG2 Catherine Snow Publications for gene: DSG2 were set to
COVID-19 research v0.347 DSG2 Catherine Snow reviewed gene: DSG2: Rating: ; Mode of pathogenicity: None; Publications: 21151137, 30862836; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.347 ATF3 Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.
PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).
PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.
PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.; to: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.

PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).

PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.

PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.
COVID-19 research v0.347 ATF3 Rebecca Foulger commented on gene: ATF3: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.
PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).
PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.
PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.
COVID-19 research v0.347 IRF1 Julie Taylor commented on gene: IRF1: Evidence Summary from Illumina curation team: IRF1 encodes interferon regulatory factor 1, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF1 is constitutively expressed at a low level but significantly elevated upon IFN-I stimulation, elevated IRF1 further amplifies the IFN response through a positive feedback loop (Lukele et al. 2019, Review). IRF-1 attenuates the replication of several viruses, including hepatitis C virus, West Nile virus (WNV), and EMCV, (Schoggins et al 2011) and IRF1 knock out mice are more susceptible to some viruses, such as EMCV and coxsackievirus B3, than wild type mice (Kimura et al. 1994). Using an IRF1 deficient BEAS2B bronchial epithelial cell line with increased susceptibility to VSV, and multiple strains of influenza viruses, Panda et al. 2019, showed that IRF1 is important for the early expression of types I and III IFNs and ISGs.
COVID-19 research v0.347 IDE Alison Coffey commented on gene: IDE: Evidence Summary from Illumina curation team: Insulin-degrading enzyme (IDE), also known as insulysin, is a member of the zinc metalloproteinase family that was initially implicated in insulin degradation. It is highly conserved among different species and has the ability to interact with a variety of functionally unrelated ligands that share little homology in their primary amino acid sequences. Several human viruses use enzymes as receptors. Li et al. (2006) (PMID 17055432) established IDE as a cellular receptor for both cell-free and cell-associated Varicella-zoster virus (VZV), the cause of chickenpox and shingles in humans. VZV is likely spread as cell-free virus to susceptible hosts but transmitted by cell-to-cell spread in the body and in vitro. Li et al. (2006) showed that IDE interacts with the VZV glycoprotein E (gE) (which is essential for virus infection) through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. Li et al. (2010) subsequently reported that a recombinant soluble IDE (rIDE) enhanced VZV infectivity at an early step of infection associated with an increase in virus internalization, and increased cell-to-cell spread. In 2017, Hahn et al. demonstrated that mature HIV-1 p6 protein (stability of which inversely affects the replication capacity of HIV-1) is a substrate for IDE. IDE is both sufficient and required for the degradation of p6, which is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. An IDE specific inhibitor, 6bK, and exogenous insulin, were both shown to interfere with X4-tropic HIV-1 replication in activated PBMCs, most probably by competing with p6 for degradation by IDE. In addition, an IDE-insensitive p6 mutant of HIV-1 exhibits impaired replication capacity but is insensitive to treatment with insulin or 6bK. Conversely, neither virus release and maturation, nor the amounts of particle associated Vpr and p6 itself were altered in IDE knock out cells. The data support a model in which IDE is responsible for the rapid degradation of p6 entering the cell as part of the incoming virion, a process that appears to be crucial to achieve optimal X4-tropic virus replication.
COVID-19 research v0.347 DEFA1 Alison Coffey commented on gene: DEFA1: Evidence Summary from Illumina curation team: DEFA1, or HNP1, is a member of the defensin family of host defense peptides, a group of microbicidal and cytotoxic peptides made by neutrophils. Defensins are known to have a role in innate immunity as a core host-protective component against bacterial, viral and fungal infections (Xu and Wuyaun, 2020). Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses. Defensins also have a potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection and are able to target multiple steps of host-virus interactions to reduce infectivity of both enveloped and non-enveloped viruses. Targets include viral envelopes, glycoproteins, and capsids or host cells. DEFA1 is well-recognized for its direct anti-HIV activity, it also restrains HIV-1 uptake by inhibiting Env-mediated viral fusion and downregulating host cell surface expression of CD4 and coreceptor CXCR4. Post-entry inhibition of enveloped viruses such as HIV-1 and influenza by DEFA1 is mediated through interfering with cell signaling pathways such as PKC that are required for viral replication (Xu and Wuyaun, 2020). An unpublished study by Kit and Kit (2020), demonstrated in silico that the affinity of human alpha-defensins 1, 2, 3 and 5 to SARS-CoV-2 spike protein is higher than that of the SARS-CoV-2 spike protein towards ACE2. The authors suggest that these alpha-defensins may serve as primary factors in protecting lung tissue from COVID-19 viral infection.
COVID-19 research v0.347 CXADR Alison Coffey commented on gene: CXADR: Evidence Summary from Illumina curation team: The coxsackie and adenovirus receptor (CXADR or CAR), also known as CAR-like membrane protein (CLMP), was first identified as a high affinity receptor for adenovirus serotypes 2 and 5 and coxsackie viruses group B. CXADR is developmentally regulated and plays an important role in cardiac development. The protein is a transmembrane receptor and plays a key role in controlling adhesion between adjacent epithelial cells. It is also implicated in controlling both recruitment of immune cells and in tumorigenesis (Zapater et al. 2017). Vehik et al. (2018) concluded that a SNP within the CXADR region is associated with islet autoimmunity. In response to exogenous TNF?, CAR promotes transmigration of leukocytes both in vitro and in vivo. suggesting that CAR may be an important receptor in the control of inflammation. As neutrophils and T cells play a role in host immunity, these data suggest that CAR may be ideally positioned to modulate the immune response from the epithelial or endothelial cell compartments. (Morton et al 2016). CAR expression and infectivity with adenovirus (Ad) are increased in cystic fibrosis airway epithelial cells (Sharma et al. 2017).
COVID-19 research v0.347 BANF1 Alison Coffey commented on gene: BANF1: Evidence Summary from Illumina curation team: BANF1 is an abundant, highly conserved DNA binding protein involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. It is also essential for early development in metazoans and relevant to human physiology. Variants in the gene are associated with Nestor-Guillermo progeria syndrome (OMIM #614008). Different viral infections can lead to changes in the subcellular distribution of BANF1 infections with a B1 kinase-deficient vaccinia virus cause re-localization at sites of viral DNA accumulation in the cytoplasm, while no change in localization is found during infection with wild-type vaccinia. By contrast, in cells infected with Herpes Simplex Virus Type-1 (HSV-1) BAF localizes to the nucleus, where HSV-1 viral DNA replicates. BANF1 actively protects the genome by intercepting foreign DNA. This protective function is exploited by retroviruses for inhibiting self-destructing autointegration of retroviral DNA, thereby promoting integration of viral DNA into the host chromosome. However, with other viruses, including the poxvirus vaccinia and HSV-1, BANF1 has an antiviral activity by blocking viral DNA replication (PMID 2607214: Jamin et al. 2015).
COVID-19 research v0.347 VPS33A Alison Coffey commented on gene: VPS33A: Evidence Summary from Illumina curation team: VPS33A is a member of the Sec1/Munc18-related (SM) protein family and a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes (Vasilev et al. 2020). Both complexes are heterohexamers and share four subunits. VPS33A, VPS11, VPS16 and VPS18, involved in endolysosomal pathway. Deficiency of VPS33A was shown to affect susceptibility to certain viruses in cell culture, including Ebola and Marburg viruses (Carette et al. 2011), however no human studies confirming this association were identified.
COVID-19 research v0.347 TLR7 Alison Coffey commented on gene: TLR7: Evidence Summary from Illumina curation team: The TLR7 gene encodes for toll -like receptor 7 protein, an endosomal receptor that plays a key role in innate and adaptive immunity. Toll-like receptors are pattern recognition receptors, which control host immune response against pathogens through recognition of molecular signatures. TLR7 recognizes uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analog (reviewed by Freund et al. 2019). Tlr7 deficient mice show an increased susceptibility to West Nile Virus (Town et al. (2009) and recently, Mukherjee et al. (2019) identified TLR7 polymorphisms associated with susceptibility to viral infections in an East Asian population Mukherjee et al. (2019).
COVID-19 research v0.347 PDGFRA Alison Coffey commented on gene: PDGFRA: Evidence Summary from Illumina curation team: The PDGFRA gene encodes the platelet-derived growth factor receptor alpha protein, a tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC, binding of which leads to the activation of several signaling cascades, and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. PDGFRA has been demonstrated to be a critical receptor for human cytomegalovirus infection (PMID 18701889: Soroceanu et al. 2008). Di Pasquale et al. (2003) (PMID 14502277). also confirmed the role of PDGFRA and PDGFRB as receptors for adeno-associated virus type 5 (AAV-5). PMID 18701889: Soroceanu et al. 2008 - PDGFRA is specifically phosphorylated by both laboratory and clinical isolates of human cytomegalovirus (CMV) in various human cell types, resulting in activation of the phosphoinositide-3-kinase signaling pathway. Cells in which PDGFRA was genetically deleted or functionally blocked were nonpermissive to human CMV entry, viral gene expression, or infectious virus production. Reintroducing the human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFRA blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited human CMV viral internalization and gene expression in human epithelial, endothelial, and fibroblast cells. Viral entry in cells harboring endogenous PDGFRA was competitively inhibited by pretreatment with PDGF-AA. It was demonstrated that human CMV glycoprotein B directly interacts with PDGFRA, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit human CMV-induced PDGFRA phosphorylation. The authors concluded that PDGFRA is a critical receptor required for human CMV infection, and thus a target for novel antiviral therapies.
COVID-19 research v0.347 NLRP6 Alison Coffey commented on gene: NLRP6: Evidence Summary from Illumina curation team: The NLRP6 gene encoding the NOD-like receptor family pyrin domain containing 6 is a member of the NLR family of proteins, that is highly expressed within the intestine and liver. The NLRP6 inflammasome plays an established role in the regulation of inflammation and host defence against microbes. Wang et al. (2015) demonstrated that NLRP6 also regulates intestinal antiviral innate immunity. NLRP6 knockout mice show increased susceptibility to infection from the single stranded RNA viruses; encephalomyocarditis virus and murine norovirus 1(MNV-1). Nlrp6 binds viral RNA via the RNA helicase Dhx15, the complex triggers the induction of type I/III interferons (IFNs) through the mitochondrial antiviral signaling protein (MAVS). Type I/III IFNs stimulate the expression of antiviral IFN-stimulated genes (ISGs), including Nlrp6 itself (Wang et al. 2015).
COVID-19 research v0.347 MX2 Alison Coffey commented on gene: MX2: Evidence Summary from Illumina curation team: MX2, also known as MXB is an interferon-induced dynamin like GTPAse with antiviral activity, which has been shown to affect the nuclear uptake and/or stability of the HIV-1 replication complex and the subsequent chromosomal integration of the proviral DNA (Goujon et al. 2013, Liu et al. 2015). However, resistance of several HIV strains to MX2-driven inhibition has been reported (Liu et al. 2015). Inhibition of other viruses, including HCV, Japanese encephalitis virus and Dengue virus of the Flaviviridae family as well as simian immunodeficiency virus and Herpesviruses has been reported (Goujon et al. 2013, Yi et al. 2019). In contrast to MX1, MX2 does not appear to be involved in regulation of several other viral infections, including influenza and Zika virus (Melen et al. 1996; Yi et al. 2019). Additionally, MX2 may be involved in nucleocytoplasmic transport and bears a nuclear localisation signal that appears essential for HCV inhibition (Melen et al. 1996; King et al. 2004, Yi et al. 2019). Of note, MX2 was described as an interferon response marker gene in preprint studies investigating expression profiles and related mechanisms in SARS-CoV-2 infection (Fagone et al. 2020, Li et al. 2020). Overall, inhibition of viral infection by MX2 appears to be virus type- and strain-specific, and some viruses potentially have developed mechanisms to resist MX2 function. No reports of any SNP associations of MX2 with viral susceptibility in humans have been identified.
COVID-19 research v0.347 KIAA0319L Alison Coffey commented on gene: KIAA0319L: Evidence Summary from Illumina curation team: KIAA0319L, also known as AAVR or AAVRL, encodes the KIAA0319 like protein, a type-I transmembrane protein which acts as an essential receptor for adeno-associated virus (AAV) and is involved in adeno-associated virus infection through endocytosis system (PMID 26814968: Pillay et al. 2016). Genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV infection. Adeno-associated virus vectors are widely used in virus-based gene therapy because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. PMID 26814968: Pillay et al. (2016) - used a haploid genetic screen to identify the type I transmembrane protein KIAA0319L as an essential receptor that mediates AAV entry and renamed this protein the AAV receptor (AAVR). The function of AAVR was confirmed by using CRISPRCas9 to knock out the receptor and by using anti-AAVR blocking antibodies; both treatments rendered cells highly resistant to AAV infection with several serotypes, including AAV2, which is the most commonly used serotype for gene therapy in clinical trials. Finally, Aavr knockout mice were more resistant to AAV-mediated gene therapy than mice that expressed AAVR. PMID 28679762: Pillay et al. (2017) - Further defines AAV-AAVR interactions, genetically and biochemically.
COVID-19 research v0.347 ITGB3 Alison Coffey commented on gene: ITGB3: Evidence Summary from Illumina curation team: ITGB3 encodes integrin beta-3 (CD61), a member of the integrin family of transmembrane proteins. Integrins are heterodimeric transmembrane proteins involved in cell adhesion and migration, and organization of the cytoskeleton. Integrin b3 has been shown to act as a coreceptor for many viruses including Herpes virus 8/HHV-8, Coxsackievirus A9, Hantaan virus, Cytomegalovirus/HHV-5, and West Nile virus (Gavrilovskaya et al. 2008; Roivainen et al. 1994; Garrigues et al 2008; Schmidt et al. 2013; Wang et al. 2005). Viruses such as the arena virus LASV and Dengue virus may manipulate and increase the expression level of ITGB3 (Zapata et al, 2013; In vitro exposure of human PBMC to a pathogenic arenavirus (LASV) increases the expression of ITGB3 (Zapata et al, 2013; Noisakran et al, 2012). Valdebenito et al. 2019 recently reported a genetic single-nucleotide polymorphism associated with infection susceptibility to Andes virus in a Chilean population.
COVID-19 research v0.347 ITGAV Alison Coffey commented on gene: ITGAV: Evidence Summary from Illumina curation team: ITGAV or ALPHA-V is a component of the integrin family of transmembrane proteins. Integrins primary biological functions involve cell adhesion and migration, organization of the cytoskeleton, and other cellular functions. Alpha-V-containing integrins combine an alpha-V subunit with 1 of 5 beta subunits. Several families of viruses are known to use alpha-V-containing integrins for cell attachment and entry, including human adenovirus type 2/5, human CMV, HIV-1, EBV, rotavirus, Coxsackievirus, and Ebola virus (Hussein et al. 2015; LaFoya et al. 2018).
COVID-19 research v0.347 ILF3 Alison Coffey commented on gene: ILF3: Evidence Summary from Illumina curation team: The ILF3 gene encodes two alternatively spliced and ubiquitously expressed RNA binding protein isoforms, NF110 and NF90. NF110 and NF90 have been shown to interact with viral RNAs and proteins to inhibit the replication of a number of viruses, including PV-RIPO, a chimeric poliovirus and human rhinovirus; HIV-1, and vesicular stomatitis virus (VSV) (reviewed Castella et al. 2015). Conversely, NF110 and NF90 have also been associated with the enhancement of viral replication in the case of DNA hepatitis B virus (HBV), ssRNA viruses from the Flaviviridae family, hepatitis C virus and influenza B (FLUBV) (reviewed Castella et al. 2015; Patzina et al, 2017). Recently, Watson et al (2020) demonstrated a role for the ILF3 isoforms in enhancing the translation of IFNB1 and ISGs in response to a viral infection. Depletion of NF90/NF110 from HeLa cells using siRNA resulted in an impaired antiviral activity with a reduction in the expression of ISG proteins and conditioned medium generated in ILF3-depleted cells conferred less resistance to Echovirus 7 infection. The specific depletion of NF110 was shown to cause a decrease in the association of IFNB1 mRNA with the polysomal fractions in poly(I:C) stimulated conditions (Watson et al. 2020).
COVID-19 research v0.347 IL9 Alison Coffey commented on gene: IL9: Evidence Summary from Illumina curation team: IL9 encodes interleukin 9, which is a stimulatory cytokine that regulates inflammatory immunity (Goswami and Kaplan 2011). It has been demonstrated that high levels of IL-9 are present in nasopharyngeal aspirate of infants with disease of the respiratory tract caused by the Human respiratory syncytial virus (RSV) (Semple et al. 2007). Studies conducted on mice showed that that the severity of lung pathology correlates with IL-9 cytokine production and that Th9 cells, which produce IL-9, play an important role in the development of airway eosinophilia and bronchial hyperresponsiveness (Dodd et al. 2009; Saeki et al. 2016). IL9 polymorphisms have also been linked to sex-restricted differences in lung function, allergen sensitization, IgE levels, and the severity of respiratory syncytial virus infection (Schuurhof et al. 2010; Aschard et al. 2009).
COVID-19 research v0.347 IL3 Alison Coffey commented on gene: IL3: Evidence Summary from Illumina curation team: IL3 encodes a growth-promoting cytokine called interleukin 3, which is a member of the beta common cytokine family. IL-3 (Dougan et al. 2019). IL-3 acts to regulate inflammation induced by pathogens as well as in autoimmune disease and cancer. T cell production of IL-3 during inflammation plays a role in the activation of plasmacytoid dendritic cells during viral infection. IL-3 has also been suggested to play a host-protective role against herpes simplex virus (HSV) infection (Chan et al. 1990).
COVID-19 research v0.347 IFNA1 Alison Coffey commented on gene: IFNA1: Evidence Summary from Illumina curation team: IFNA1 encodes IFN alpha, and belongs to the family of type I IFNs which bind to and activate the IFNAR receptor complex. Type I Interferons (IFN-I) mediate numerous immune interactions during viral infections, they establish an antiviral state as well as invoke and regulate innate and adaptive immune cells that eliminate infection (Lukele et al. 2019, review; Wang et al.2019 review).
COVID-19 research v0.347 HAVCR1 Alison Coffey commented on gene: HAVCR1: Evidence Summary from Illumina curation team: HAVCR1 encodes the human hepatitis A virus (HAV) cellular receptor 1 (CD365, TIM1, KIM1) a phospholipid receptor which is expressed in mucosal epthelium from a range of tissues including trachea, conjunctiva and cornea (Kondratowicz et al. 2011). HAVCR1 acts as a cell receptor or entry factor for a number of enveloped viruses including Hepatitis A, Ebolavirus, Marberg virus and Dengue virus (Kondratowicz et al. 2011; Costfreda et al. 2018; Meertens et al. 2012).
COVID-19 research v0.347 GPR183 Alison Coffey commented on gene: GPR183: Evidence Summary from Illumina curation team: The GPR183 gene has been shown to be upregulated following infection with Epstein-Barr virus and aids in leukocyte migration into airways in response to allergens (Shen et al. 2017). GPR183 knockout mice exhibit enhanced pro-inflammatory cytokine release following an inflammation-inducing stimulus (Ruthiwska et al. 2018). In addition, recent work that has not yet been peer-reviewed found GPR183 expression on macrophages in severe Covid 19 patients (Liao et al.; https://doi.org/10.1101/2020.02.23.20026690). EBV seropositivity was also associated with fever and increased inflammation in Covid 19 patients in non-peer-reviewed work by Chen et al. (10.21203/rs.3.rs-21580/v1).
COVID-19 research v0.347 GPATCH3 Alison Coffey commented on gene: GPATCH3: Evidence Summary from Illumina curation team: Nie et al. (2017) showed that GPATCH3 is a negative regulator of the innate immune response to RNA viruses. Reduction of GPATCH3 levels using shRNA resulted in enhanced induction and transcription of SeV (ssRNA virus) downstream antiviral genes such as IFNB1, in multiple cell lines compared to controls. Similar effects were not observed in cells infected with DNA viruses, HCMV or HSV120. Coimmunoprecipitation and colocalisation experiments indicated that GPATCH3 negative regulation is mediated through a direct interaction of mitochondrial localised, MAVS (VISA). MAVS plays an established role in the innate antiviral immune responses against to RNA viruses.
COVID-19 research v0.347 GNAQ Alison Coffey commented on gene: GNAQ: Evidence Summary from Illumina curation team: The GNAQ gene encodes the Gq protein alpha subunit and belongs to the Gq/11 subfamily of heterotrimeric G proteins. GNAQ is ubiquitously expressed in mammalian cells and couples a wide variety of receptors to channel proteins, enzymes, and other effector molecules. Wang et al. (2019) found that Gnaq expression was downregulated during viral infection and that Gnaq siRNA transfection of host cells protected against infection from vesicular stomatitis virus (VSV) and HSV type 1 infection. Viral replication was also reduced in Gnaq deficient macrophages in cell culture and Gnaq-deficient mice were more resistant than wildtype mice to VSV infection. Further cell culture experiments showed that Gnaq modulated its antiviral response through the canonical PLC-b/Ca2+ signalling (Wang et al. 2019). PMID: 31324725 Wang et al. (2019) - Wang et al. demonstrated that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. Viral infection downregulates GNAQ expression in cell culture. mRNA expression levels were measured upon infection with VSV in mouse PEMs, BMMs,the fibroblast line L929 and the macrophage mouse line RAW264.7. Fig1. GNAQ negatively regulates host defence against viruses. Gnaq-specific siRNA knockdown reduced VSV infection in PEMS, overexpression of GNAQ in HEK293 cells increased VSV infection (Fig 2). PEMS and BMMs from myeloid cellspecific Gnaq-deficient mice showed reduced replication of VSV and HSV1 compared to WT. VSV replication and titers in the liver, spleen, and lung of Gnaq-deficient mice were all significantly lower than wt litter mates. Gnaq deficiency increases host resistance to viral infection (Fig 3). IFN-b (both mRNA and protein) was significantly enhanced in Gnaq-knockdown PEMs, Poly I;C (mimicking RNA viral infection), VSV infection and HSV-1 infection enhanced IgnBeta production in Gnaq-knockdown PEMs. In cell lines and in vivo, GNAQ negatively regulates IFN-beta production (Fig 4). GNAQ modulates antiviral innate immune responses through canonical PLC-b/Ca2+ signalling. Chemical inhibitors of the pathway reduced cell resistance to infection (Fig 5).
COVID-19 research v0.347 CLDN9 Alison Coffey commented on gene: CLDN9: Evidence Summary from Illumina curation team: CLDN9 gene encodes for the Claudin-9 protein. The claudin family constitutes a large group of four- transmembrane domain proteins that are essential for the formation of tight junctions responsible for the control of paracellular transport. Studies have demonstrated that CLDN9 and CLDN6 mediate the entry of the hepatitis C virus (HCV) into both hepatic and non-hepatic cell lines (Zheng et al. 2007) however, HCV infection is not dependent on the presence of CLDN9 (Fofana et al. 2013).
COVID-19 research v0.347 CLDN6 Alison Coffey commented on gene: CLDN6: Evidence Summary from Illumina curation team: CLDN6 gene encodes the Claudin-6 protein. The claudin family constitutes of a large group of four- transmembrane domain proteins that are essential for the formation of tight junctions responsible for the control of paracellular transport. Studies have demonstrated that CLDN6 and CLDN9 mediate the entry of the Hepatitis C virus (HCV) into both liver and non-liver cells (Zheng et al. 2007) however, HCV infection is not dependent on the presence of CLDN6 (Haid et al. 2014; Fofana et al. 2013).
COVID-19 research v0.347 CDKN1B Alison Coffey commented on gene: CDKN1B: Evidence Summary from Illumina curation team: CDKN1B, or p27(KIP1), is a cyclin-dependent kinase inhibitor that blocks the cell cycle in the G0/G1 phase upon differentiation signals or cellular insult (OMIM 600778). Karlas et al. (2010) identified p27/KIP as an inhibitor of influenza A viral replication in a genomewide RNA interference screen. The result was validated in the p27/KIP knockout mouse model, the viral load within these mice was significantly reduced two days after infection compared to control mice.
COVID-19 research v0.347 CD207 Alison Coffey commented on gene: CD207: Evidence Summary from Illumina curation team: The CD207 gene encodes the CD207 protein, also known as langerin, a cell surface C-type lectin expressed on Langerhans cells, the immature dendritic cells of the epidermis and mucosa. CD207 has a role as a pattern recognition receptor for a number of viruses including the Influenza A Virus (Ng et al. 2016), HIV-1 and HSV (reviewed by de Jong et al. 2010) and measles virus (van der Vlist et al. 2011).
COVID-19 research v0.347 CCR7 Alison Coffey commented on gene: CCR7: Evidence Summary from Illumina curation team: The CCR7 gene encodes the C-C chemokine receptor 7, a chemokine receptor which is a member of the G protein-coupled receptor superfamily. CCR7 plays an important role in the homing of central memory and nave T cells to peripheral lymphoid organs. The binding of CCR7 ligands CCL19 and CCL21 during viral infection promotes activation and differentiation of CCR7 expressing cells, as well as changes in their migration properties to modulate the immune response (reviewed Yan et al. 2019). Some viral proteins target CCR7 and reduce its expression during viral infection (reviewed Yan et al. 2019), for example, the HIV-1 accessory protein, Vpu, interacts directly with CCR7 to cause its retention within the trans Golgi network of primary CD4+ T cells (Ramirez et al. 2014).
COVID-19 research v0.347 ATG5 Alison Coffey commented on gene: ATG5: Evidence Summary from Illumina curation team: The ATG5 gene encodes a core autophagy protein which forms a complex with ATG12 and ATG16L that is important for autophagophore elongation. Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al.2018). ATG5 may play a role in cytokine regulation, in vitro, ATG5 depleted primary human blood macrophages produced lower levels of CXCL10 and IFNa when infected with influenza A virus (Law et al. 2007). ATG5 deficient mice also show reduced Ifn and Il22 secretion when infected with the single stranded RNA vesicular stomatitis virus (VSV) (Lee et al. 2007). Using a mouse model with a conditional depletion of ATG5 within dendritic cells, Lee et al. 2010 showed that ATG5 is required for antigen presentation by dendritic cells, as a result of reduced MHC-II antigen presentation, these mice, when intradermally injected with HSV-1, showed significantly lower IFNgamma production by CD4+ T cells. (Lee et al., 2010). The ATG5 complex is targeted by some viruses to enhance infection, for example, the foot and mouth disease virus (FMDV) targets the ATG5-ATG12 complex for degradation through its viral protein 3Cpro, similarly, depletion of ATG5 and ATG12 in vitro, by siRNA increased susceptibility to FMDV infection by reducing activation of the NF-?B and IRF3 pathways (Fan et al 2017).
COVID-19 research v0.347 ATG16L1 Alison Coffey commented on gene: ATG16L1: Evidence Summary from Illumina curation team: The ATG16L gene encodes a core autophagy protein which forms a complex with ATG5 and ATG12 that is important for autophagophore elongation (Lavoie et al. 2019). Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al. 2018). The ATG16L complex is also targeted by some viruses to enhance infection. The Zika virus protease, targets ATG16L, dramatically depleting its levels during Zika virus infection (Hill et al. 2018). Conversely, Hepatitis B virus (HBV), an enveloped pararetrovirus, stimulates autophagy to favor its production. In vitro, RNA interference-mediated silencing of Atg16L1 interfered with viral core/nucleocapsid (NC) formation and stability, strongly diminishing virus replication (Fletcher et al. 2018).
COVID-19 research v0.347 AIM2 Alison Coffey commented on gene: AIM2: Evidence summary from Illumina curation team: AIM2 performs an established role within the innate immune system as a pattern recognition receptor which senses microbial dsDNA. In vitro experiments have shown that AIM2 recognises cytosolic dsDNA from a number of viruses and consequently drives pyroptosis through formation of an inflammasome complex (Sharma et al. 2019). Aim2-deficient mice show an attenuated immune response upon infection with mCNV when compared to wildtype mice (Rathinam et al. 2010). PMID: 31372985 Sharma et al. 2019 (Review) AIM2 encodes a pattern recognition receptor which senses microbial dsDNA. In vitro experiments show AIM2 recognises cytosolic dsDNA from a number of viruses and consequently drives pyroptosis through formation of an inflammasome complex. AIM2 expression is upregulated in response to infection by RNA viruses and contributes to secretion of IL-1beta, the mechanism for the recognition of RNA viruses is unclear. Table 1 summarises the list of in vitro AIM2 virus studies. PMID: 20351692: Rathinam et al. 2010 In vivo, Aim2-deficient mice, Aim2- infected with mCMV have reduced IL-18 concentrations in the serum compared to wildtype mice, and severely attenuated IFN-? production by NK cells, events, which are critical for the early control of viral replication (Figure 7b, d, e) The spleen of infected Aim2-/- mice demonstrated elevated viral titre compared to the wildtype (Fig 7h, i). PMID: 26590313 Schattgen et al. 2018 Aim2 knockout mice, infected with influenza A virus (RNA virus) showed an exaggerated response to immune response. Authors suggest that host DNA released from damaged cells during IAV infection and sensed by AIM2 leads to limitation of immune mediated damage to infected tissues.
COVID-19 research v0.346 CXCR3 Catherine Snow Publications for gene: CXCR3 were set to 27412416; 19039768; 30109979; 26318079; 30467622
COVID-19 research v0.345 CXCR3 Catherine Snow Publications for gene: CXCR3 were set to
COVID-19 research v0.344 CXCR3 Catherine Snow reviewed gene: CXCR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27412416, 19039768, 30109979, 26318079, 30467622; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.344 ATG16L1 Rebecca Foulger Publications for gene: ATG16L1 were set to
COVID-19 research v0.343 ATG16L1 Rebecca Foulger Classified gene: ATG16L1 as Amber List (moderate evidence)
COVID-19 research v0.343 ATG16L1 Rebecca Foulger Gene: atg16l1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.342 ATG16L1 Rebecca Foulger Classified gene: ATG16L1 as Red List (low evidence)
COVID-19 research v0.342 ATG16L1 Rebecca Foulger Added comment: Comment on list classification: Gene was originally added to panel as Red following initial triage by Illumina curation team (Alison Coffey and Julie Taylor). Updated rating to Amber to match revised Illumina review after literature curation.
COVID-19 research v0.342 ATG16L1 Rebecca Foulger Gene: atg16l1 has been classified as Red List (Low Evidence).
COVID-19 research v0.341 IRF1 Julie Taylor reviewed gene: IRF1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31155227, 31156620, 24719409, 21478870, 80092222; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IDE Alison Coffey reviewed gene: IDE: Rating: AMBER; Mode of pathogenicity: ; Publications: 17055432, 20593027, 28388673; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 HDAC6 Alison Coffey reviewed gene: HDAC6: Rating: GREEN; Mode of pathogenicity: ; Publications: 27959772, 31736889, 26746851, 25482409; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 DEFA1 Alison Coffey reviewed gene: DEFA1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32457744; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 DAG1 Alison Coffey reviewed gene: DAG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 16254364, 19324387, 17360738, 21185048:15857984; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CXADR Alison Coffey reviewed gene: CXADR: Rating: AMBER; Mode of pathogenicity: ; Publications: 28545889, 31792456, 27527752, 27193388; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 BECN1 Alison Coffey reviewed gene: BECN1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32265919, 19635843, 18248095, 18005679; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 BANF1 Alison Coffey reviewed gene: BANF1: Rating: RED; Mode of pathogenicity: ; Publications: 2607214; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CXCL8 Alison Coffey reviewed gene: CXCL8: Rating: GREEN; Mode of pathogenicity: ; Publications: 3244677, 32161940, 15585888; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 VPS33A Alison Coffey reviewed gene: VPS33A: Rating: RED; Mode of pathogenicity: ; Publications: 21866103, 31936524; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 VPS11 Alison Coffey reviewed gene: VPS11: Rating: RED; Mode of pathogenicity: ; Publications: 21866103, 25375324, 26953343, 26958914; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 TLR7 Alison Coffey reviewed gene: TLR7: Rating: GREEN; Mode of pathogenicity: ; Publications: 19200759, 31481269, 29964062, 30699960; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 RNASEL Alison Coffey reviewed gene: RNASEL: Rating: GREEN; Mode of pathogenicity: ; Publications: 27595182, 16235172, 20479874, 9351818, 31156620, 22356654; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 PVR Alison Coffey reviewed gene: PVR: Rating: AMBER; Mode of pathogenicity: ; Publications: 28870470, 25113908, 19815499, 12943679, 17621371, 28800489, 2597248; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 PTX3 Alison Coffey reviewed gene: PTX3: Rating: AMBER; Mode of pathogenicity: ; Publications: 31031772, 18292565, 25695775, 18292565, 19968561; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 PDGFRA Alison Coffey reviewed gene: PDGFRA: Rating: AMBER; Mode of pathogenicity: ; Publications: 18701889, 14502277; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 NPC1 Alison Coffey reviewed gene: NPC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 21866103, 2186610, 26771495, 27238017; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 NLRP6 Alison Coffey reviewed gene: NLRP6: Rating: AMBER; Mode of pathogenicity: ; Publications: 26494172, 32386845 ; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 NECTIN1 Alison Coffey reviewed gene: NECTIN1: Rating: AMBER; Mode of pathogenicity: ; Publications: 1175687, 12072525, 19805039; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 MX2 Alison Coffey reviewed gene: MX2: Rating: AMBER; Mode of pathogenicity: ; Publications: 24048477, 25571928, 30333168, 8798556, 15184662, 32345362 ; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 MIR155 Alison Coffey reviewed gene: MIR155: Rating: AMBER; Mode of pathogenicity: ; Publications: 32233818, 217121651, 1746328969, 20852130, 28139244, 23686237, 26072128, 32308197, 23601686, 23275599, 24516198; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 KLF2 Alison Coffey reviewed gene: KLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 17141159, 19592277, 22988032, 29125549, 27855271; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 KIAA0319L Alison Coffey reviewed gene: KIAA0319L: Rating: GREEN; Mode of pathogenicity: ; Publications: 26814968, 28679762; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ITGB3 Alison Coffey reviewed gene: ITGB3: Rating: GREEN; Mode of pathogenicity: ; Publications: 9618541, 7519807, 18045938, 23658209, 15834425, 22987294, 24069471, 30791508; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ITGAV Alison Coffey reviewed gene: ITGAV: Rating: GREEN; Mode of pathogenicity: ; Publications: 29393909, 26321473; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IRF2 Alison Coffey reviewed gene: IRF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31155227, 21478870, 22615998, 8402903, 10208925, 22113474, 27899441; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ILF3 Alison Coffey reviewed gene: ILF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 25327818, 31701124, 28869005; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IL9 Alison Coffey reviewed gene: IL9: Rating: AMBER; Mode of pathogenicity: ; Publications: 21368237, 17940602, 19915054, 27297515, 20503287, 19536153; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IL3 Alison Coffey reviewed gene: IL3: Rating: AMBER; Mode of pathogenicity: ; Publications: 2176641, 30995500; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IFNE Alison Coffey reviewed gene: IFNE: Rating: GREEN; Mode of pathogenicity: ; Publications: 31734130, 23449591, 28045025, 29187603; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IFNA1 Alison Coffey reviewed gene: IFNA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31155227, 31771760; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 HAVCR1 Alison Coffey reviewed gene: HAVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23084921, 29321304, 29437974, 21536871, 9658108; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 GPR183 Alison Coffey reviewed gene: GPR183: Rating: AMBER; Mode of pathogenicity: ; Publications: 29374507, 28125291, preprint: https://doi.org/10.1101/2020.02.23.20026690, preprint: 10.21203/rs.3.rs-21580/v1; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 GPATCH3 Alison Coffey reviewed gene: GPATCH3: Rating: AMBER; Mode of pathogenicity: ; Publications: 28414768; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 GNAQ Alison Coffey reviewed gene: GNAQ: Rating: AMBER; Mode of pathogenicity: ; Publications: 31324725; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 FOLR1 Alison Coffey reviewed gene: FOLR1: Rating: AMBER; Mode of pathogenicity: ; Publications: 11461707, preprint: https://doi.org/10.1101/618306; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 DICER1 Alison Coffey reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: ; Publications: 17181864, 18325616, 26085159, 24303839, 28591694, 30015086, 25176334, 16554838, 21385408, 32141569, 23849790, 25883138, 24115437, 27273616, 30872283, 30682089, 32291557, 16009718, 17613256, 22438534, 28473628; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CLDN9 Alison Coffey reviewed gene: CLDN9: Rating: RED; Mode of pathogenicity: ; Publications: 17804490, 23864633; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CLDN6 Alison Coffey reviewed gene: CLDN6: Rating: RED; Mode of pathogenicity: ; Publications: 17804490, 23775920, 23864633; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CDKN1B Alison Coffey reviewed gene: CDKN1B: Rating: RED; Mode of pathogenicity: ; Publications: 20081832; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CD28 Alison Coffey reviewed gene: CD28: Rating: AMBER; Mode of pathogenicity: ; Publications: 29329537, 32299202; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CD207 Alison Coffey reviewed gene: CD207: Rating: AMBER; Mode of pathogenicity: ; Publications: 21030306, 21739428, 26468543; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CCR7 Alison Coffey reviewed gene: CCR7: Rating: AMBER; Mode of pathogenicity: ; Publications: 31632965, 24910430; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CCR2 Alison Coffey reviewed gene: CCR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 21131425, 30498200, 28178200, 31777682; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ATG5 Alison Coffey reviewed gene: ATG5: Rating: AMBER; Mode of pathogenicity: ; Publications: 30510929, 32265919, 28102839, 20473322, 20171125, 17272685; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ATG16L1 Alison Coffey reviewed gene: ATG16L1: Rating: AMBER; Mode of pathogenicity: ; Publications: 30666959, 29367244, 32265919, 30510929; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ATF3 Alison Coffey reviewed gene: ATF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 28355270, 28821775, 26416280; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 AIM2 Alison Coffey reviewed gene: AIM2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31372985, 20351692, 26590313; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.340 FEZ1 Ivone Leong Publications for gene: FEZ1 were set to
COVID-19 research v0.339 DEFA1 Rebecca Foulger commented on gene: DEFA1
COVID-19 research v0.339 CXCL8 Rebecca Foulger commented on gene: CXCL8
COVID-19 research v0.339 MX2 Rebecca Foulger commented on gene: MX2
COVID-19 research v0.339 HAVCR1 Rebecca Foulger commented on gene: HAVCR1
COVID-19 research v0.339 DEFA1 Rebecca Foulger gene: DEFA1 was added
gene: DEFA1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: DEFA1 was set to Unknown
Publications for gene: DEFA1 were set to 32457744
COVID-19 research v0.339 CXCL8 Rebecca Foulger gene: CXCL8 was added
gene: CXCL8 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CXCL8 was set to Unknown
Publications for gene: CXCL8 were set to 15585888; 32161940; 3244677
COVID-19 research v0.339 MX2 Rebecca Foulger gene: MX2 was added
gene: MX2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: MX2 was set to Unknown
Publications for gene: MX2 were set to 15184662; 24048477; 25571928; 8798556; 32345362; 30333168
COVID-19 research v0.339 HAVCR1 Rebecca Foulger gene: HAVCR1 was added
gene: HAVCR1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: HAVCR1 was set to Unknown
Publications for gene: HAVCR1 were set to 29321304; 21536871; 23084921; 29437974; 9658108
COVID-19 research v0.338 CD244 Ivone Leong reviewed gene: CD244: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.338 CD200 Sarah Leigh gene: CD200 was added
gene: CD200 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: CD200 was set to Unknown
COVID-19 research v0.338 VPS4A Sarah Leigh gene: VPS4A was added
gene: VPS4A was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: VPS4A was set to Unknown
COVID-19 research v0.338 TPH1 Sarah Leigh gene: TPH1 was added
gene: TPH1 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TPH1 was set to Unknown
COVID-19 research v0.338 TNFSF4 Sarah Leigh gene: TNFSF4 was added
gene: TNFSF4 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TNFSF4 was set to Unknown
Phenotypes for gene: TNFSF4 were set to {Myocardial infarction, susceptibility to} 608446
COVID-19 research v0.338 TLR5 Sarah Leigh gene: TLR5 was added
gene: TLR5 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TLR5 was set to Unknown
Phenotypes for gene: TLR5 were set to {Legionnaire disease, susceptibility to} 608556
COVID-19 research v0.338 TLR4 Sarah Leigh gene: TLR4 was added
gene: TLR4 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TLR4 was set to Unknown
COVID-19 research v0.337 CD244 Ivone Leong Publications for gene: CD244 were set to
COVID-19 research v0.336 CASP1 Ivone Leong reviewed gene: CASP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.336 IRF1 Rebecca Foulger commented on gene: IRF1
COVID-19 research v0.336 IDE Rebecca Foulger commented on gene: IDE
COVID-19 research v0.336 HDAC6 Rebecca Foulger commented on gene: HDAC6
COVID-19 research v0.336 FEZ1 Rebecca Foulger commented on gene: FEZ1
COVID-19 research v0.336 DSG2 Rebecca Foulger commented on gene: DSG2
COVID-19 research v0.336 DAG1 Rebecca Foulger commented on gene: DAG1
COVID-19 research v0.336 CXADR Rebecca Foulger commented on gene: CXADR
COVID-19 research v0.336 BECN1 Rebecca Foulger commented on gene: BECN1
COVID-19 research v0.336 BANF1 Rebecca Foulger commented on gene: BANF1
COVID-19 research v0.336 ABCC1 Rebecca Foulger commented on gene: ABCC1
COVID-19 research v0.336 ABCB1 Rebecca Foulger commented on gene: ABCB1
COVID-19 research v0.336 FCMR Rebecca Foulger commented on gene: FCMR
COVID-19 research v0.336 VPS33A Rebecca Foulger commented on gene: VPS33A
COVID-19 research v0.336 VPS11 Rebecca Foulger commented on gene: VPS11
COVID-19 research v0.336 TNFSF10 Rebecca Foulger commented on gene: TNFSF10
COVID-19 research v0.336 TLR7 Rebecca Foulger commented on gene: TLR7
COVID-19 research v0.336 RNASEL Rebecca Foulger commented on gene: RNASEL
COVID-19 research v0.336 PVR Rebecca Foulger commented on gene: PVR
COVID-19 research v0.336 PTX3 Rebecca Foulger commented on gene: PTX3
COVID-19 research v0.336 PDGFRA Rebecca Foulger commented on gene: PDGFRA
COVID-19 research v0.336 NPC1 Rebecca Foulger commented on gene: NPC1
COVID-19 research v0.336 NLRP6 Rebecca Foulger commented on gene: NLRP6
COVID-19 research v0.336 NECTIN1 Rebecca Foulger commented on gene: NECTIN1
COVID-19 research v0.336 MIR155 Rebecca Foulger commented on gene: MIR155
COVID-19 research v0.336 KLF2 Rebecca Foulger commented on gene: KLF2
COVID-19 research v0.336 KIAA0319L Rebecca Foulger commented on gene: KIAA0319L
COVID-19 research v0.336 ITGB3 Rebecca Foulger commented on gene: ITGB3
COVID-19 research v0.336 ITGAV Rebecca Foulger commented on gene: ITGAV
COVID-19 research v0.336 IRF2 Rebecca Foulger commented on gene: IRF2
COVID-19 research v0.336 ILF3 Rebecca Foulger commented on gene: ILF3
COVID-19 research v0.336 IL9 Rebecca Foulger commented on gene: IL9
COVID-19 research v0.336 IL3 Rebecca Foulger commented on gene: IL3
COVID-19 research v0.336 IFNE Rebecca Foulger commented on gene: IFNE
COVID-19 research v0.336 IFNA1 Rebecca Foulger commented on gene: IFNA1
COVID-19 research v0.336 GPR183 Rebecca Foulger commented on gene: GPR183
COVID-19 research v0.336 GPATCH3 Rebecca Foulger commented on gene: GPATCH3
COVID-19 research v0.336 GNAQ Rebecca Foulger commented on gene: GNAQ
COVID-19 research v0.336 FOLR1 Rebecca Foulger commented on gene: FOLR1
COVID-19 research v0.336 EIF3M Rebecca Foulger commented on gene: EIF3M
COVID-19 research v0.336 EGFR Rebecca Foulger commented on gene: EGFR
COVID-19 research v0.336 DICER1 Rebecca Foulger commented on gene: DICER1
COVID-19 research v0.336 CXCR3 Rebecca Foulger commented on gene: CXCR3
COVID-19 research v0.336 CLDN9 Rebecca Foulger commented on gene: CLDN9
COVID-19 research v0.336 CLDN6 Rebecca Foulger commented on gene: CLDN6
COVID-19 research v0.336 CDKN1B Rebecca Foulger commented on gene: CDKN1B
COVID-19 research v0.336 CD28 Rebecca Foulger commented on gene: CD28
COVID-19 research v0.336 CD244 Rebecca Foulger commented on gene: CD244
COVID-19 research v0.336 CD207 Rebecca Foulger commented on gene: CD207
COVID-19 research v0.336 CCR7 Rebecca Foulger commented on gene: CCR7
COVID-19 research v0.336 CCR2 Rebecca Foulger commented on gene: CCR2
COVID-19 research v0.336 CASP1 Rebecca Foulger commented on gene: CASP1
COVID-19 research v0.336 ATG5 Rebecca Foulger commented on gene: ATG5
COVID-19 research v0.336 ATG16L1 Rebecca Foulger commented on gene: ATG16L1
COVID-19 research v0.336 ATF3 Rebecca Foulger commented on gene: ATF3
COVID-19 research v0.336 AIM2 Rebecca Foulger commented on gene: AIM2
COVID-19 research v0.335 CASP1 Ivone Leong Publications for gene: CASP1 were set to
COVID-19 research v0.334 ABCC1 Ivone Leong reviewed gene: ABCC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.334 ABCB1 Ivone Leong edited their review of gene: ABCB1: Added comment: Searching through PubMed, most of the papers related to ABCB1 are to do with drug efficacy and ABCB1's affect on HIV-1 treatments. Therefore, this gene should remain rated Red.; Changed rating: RED
COVID-19 research v0.334 ABCB1 Ivone Leong Added comment: Comment on publications: PMID: 18547906 showed that ABCB1 SNP (C3435T) is associated with virological efficacy in treatments for HIV infected pateints.

PMID: 26922556 showed that SNPS in ABCB1 may influence HCV infectivity.
COVID-19 research v0.334 ABCB1 Ivone Leong Publications for gene: ABCB1 were set to
COVID-19 research v0.333 IRF1 Rebecca Foulger gene: IRF1 was added
gene: IRF1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IRF1 was set to Unknown
COVID-19 research v0.333 IDE Rebecca Foulger gene: IDE was added
gene: IDE was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: IDE was set to Unknown
COVID-19 research v0.333 HDAC6 Rebecca Foulger gene: HDAC6 was added
gene: HDAC6 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: HDAC6 was set to Unknown
COVID-19 research v0.333 FEZ1 Rebecca Foulger gene: FEZ1 was added
gene: FEZ1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: FEZ1 was set to Unknown
COVID-19 research v0.333 DSG2 Rebecca Foulger gene: DSG2 was added
gene: DSG2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: DSG2 was set to Unknown
COVID-19 research v0.333 DAG1 Rebecca Foulger gene: DAG1 was added
gene: DAG1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: DAG1 was set to Unknown
COVID-19 research v0.333 CXADR Rebecca Foulger gene: CXADR was added
gene: CXADR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CXADR was set to Unknown
COVID-19 research v0.333 BECN1 Rebecca Foulger gene: BECN1 was added
gene: BECN1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: BECN1 was set to Unknown
COVID-19 research v0.333 BANF1 Rebecca Foulger gene: BANF1 was added
gene: BANF1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: BANF1 was set to Unknown
COVID-19 research v0.333 ABCC1 Rebecca Foulger gene: ABCC1 was added
gene: ABCC1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: ABCC1 was set to Unknown
COVID-19 research v0.333 ABCB1 Rebecca Foulger gene: ABCB1 was added
gene: ABCB1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: ABCB1 was set to Unknown
COVID-19 research v0.333 FCMR Rebecca Foulger gene: FCMR was added
gene: FCMR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: FCMR was set to Unknown
COVID-19 research v0.333 VPS33A Rebecca Foulger gene: VPS33A was added
gene: VPS33A was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: VPS33A was set to Unknown
COVID-19 research v0.333 VPS11 Rebecca Foulger gene: VPS11 was added
gene: VPS11 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: VPS11 was set to Unknown
COVID-19 research v0.333 TNFSF10 Rebecca Foulger gene: TNFSF10 was added
gene: TNFSF10 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: TNFSF10 was set to Unknown
COVID-19 research v0.333 TLR7 Rebecca Foulger gene: TLR7 was added
gene: TLR7 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: TLR7 was set to Unknown
COVID-19 research v0.333 RNASEL Rebecca Foulger gene: RNASEL was added
gene: RNASEL was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: RNASEL was set to Unknown
COVID-19 research v0.333 PVR Rebecca Foulger gene: PVR was added
gene: PVR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: PVR was set to Unknown
COVID-19 research v0.333 PTX3 Rebecca Foulger gene: PTX3 was added
gene: PTX3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: PTX3 was set to Unknown
COVID-19 research v0.333 PDGFRA Rebecca Foulger gene: PDGFRA was added
gene: PDGFRA was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: PDGFRA was set to Unknown
COVID-19 research v0.333 NPC1 Rebecca Foulger gene: NPC1 was added
gene: NPC1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: NPC1 was set to Unknown
COVID-19 research v0.333 NLRP6 Rebecca Foulger gene: NLRP6 was added
gene: NLRP6 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: NLRP6 was set to Unknown
COVID-19 research v0.333 NECTIN1 Rebecca Foulger gene: NECTIN1 was added
gene: NECTIN1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: NECTIN1 was set to Unknown
COVID-19 research v0.333 MIR155 Rebecca Foulger gene: MIR155 was added
gene: MIR155 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: MIR155 was set to Unknown
COVID-19 research v0.333 KLF2 Rebecca Foulger gene: KLF2 was added
gene: KLF2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: KLF2 was set to Unknown
COVID-19 research v0.333 KIAA0319L Rebecca Foulger gene: KIAA0319L was added
gene: KIAA0319L was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: KIAA0319L was set to Unknown
COVID-19 research v0.333 ITGB3 Rebecca Foulger gene: ITGB3 was added
gene: ITGB3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: ITGB3 was set to Unknown
COVID-19 research v0.333 ITGAV Rebecca Foulger gene: ITGAV was added
gene: ITGAV was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: ITGAV was set to Unknown
COVID-19 research v0.333 IRF2 Rebecca Foulger gene: IRF2 was added
gene: IRF2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IRF2 was set to Unknown
COVID-19 research v0.333 ILF3 Rebecca Foulger gene: ILF3 was added
gene: ILF3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: ILF3 was set to Unknown
COVID-19 research v0.333 IL9 Rebecca Foulger gene: IL9 was added
gene: IL9 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: IL9 was set to Unknown
COVID-19 research v0.333 IL3 Rebecca Foulger gene: IL3 was added
gene: IL3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: IL3 was set to Unknown
COVID-19 research v0.333 IFNE Rebecca Foulger gene: IFNE was added
gene: IFNE was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IFNE was set to Unknown
COVID-19 research v0.333 IFNA1 Rebecca Foulger gene: IFNA1 was added
gene: IFNA1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IFNA1 was set to Unknown
COVID-19 research v0.333 GPR183 Rebecca Foulger gene: GPR183 was added
gene: GPR183 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: GPR183 was set to Unknown
COVID-19 research v0.333 GPATCH3 Rebecca Foulger gene: GPATCH3 was added
gene: GPATCH3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: GPATCH3 was set to Unknown
COVID-19 research v0.333 GNAQ Rebecca Foulger gene: GNAQ was added
gene: GNAQ was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: GNAQ was set to Unknown
COVID-19 research v0.333 FOLR1 Rebecca Foulger gene: FOLR1 was added
gene: FOLR1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: FOLR1 was set to Unknown
COVID-19 research v0.333 EIF3M Rebecca Foulger gene: EIF3M was added
gene: EIF3M was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: EIF3M was set to Unknown
COVID-19 research v0.333 EGFR Rebecca Foulger gene: EGFR was added
gene: EGFR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: EGFR was set to Unknown
COVID-19 research v0.333 DICER1 Rebecca Foulger gene: DICER1 was added
gene: DICER1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: DICER1 was set to Unknown
COVID-19 research v0.333 CXCR3 Rebecca Foulger gene: CXCR3 was added
gene: CXCR3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CXCR3 was set to Unknown
COVID-19 research v0.333 CLDN9 Rebecca Foulger gene: CLDN9 was added
gene: CLDN9 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CLDN9 was set to Unknown
COVID-19 research v0.333 CLDN6 Rebecca Foulger gene: CLDN6 was added
gene: CLDN6 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CLDN6 was set to Unknown
COVID-19 research v0.333 CDKN1B Rebecca Foulger gene: CDKN1B was added
gene: CDKN1B was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CDKN1B was set to Unknown
COVID-19 research v0.333 CD28 Rebecca Foulger gene: CD28 was added
gene: CD28 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CD28 was set to Unknown
COVID-19 research v0.333 CD244 Rebecca Foulger gene: CD244 was added
gene: CD244 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CD244 was set to Unknown
COVID-19 research v0.333 CD207 Rebecca Foulger gene: CD207 was added
gene: CD207 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CD207 was set to Unknown
COVID-19 research v0.333 CCR7 Rebecca Foulger gene: CCR7 was added
gene: CCR7 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CCR7 was set to Unknown
COVID-19 research v0.333 CCR2 Rebecca Foulger gene: CCR2 was added
gene: CCR2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CCR2 was set to Unknown
COVID-19 research v0.333 CASP1 Rebecca Foulger gene: CASP1 was added
gene: CASP1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CASP1 was set to Unknown
COVID-19 research v0.333 ATG5 Rebecca Foulger gene: ATG5 was added
gene: ATG5 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: ATG5 was set to Unknown
COVID-19 research v0.333 ATG16L1 Rebecca Foulger gene: ATG16L1 was added
gene: ATG16L1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: ATG16L1 was set to Unknown
COVID-19 research v0.333 ATF3 Rebecca Foulger gene: ATF3 was added
gene: ATF3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: ATF3 was set to Unknown
COVID-19 research v0.333 AIM2 Rebecca Foulger gene: AIM2 was added
gene: AIM2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: AIM2 was set to Unknown
Rhabdomyolysis and metabolic muscle disorders v1.39 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
COVID-19 research v0.332 ACE2 Catherine Snow reviewed gene: ACE2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.332 ZFHX3 Sarah Leigh edited their review of gene: ZFHX3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 WSCD1 Sarah Leigh edited their review of gene: WSCD1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 UNC5CL Sarah Leigh edited their review of gene: UNC5CL: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 TAPT1 Sarah Leigh edited their review of gene: TAPT1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 SPNS3 Sarah Leigh edited their review of gene: SPNS3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 RPAIN Sarah Leigh edited their review of gene: RPAIN: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 PROM1 Sarah Leigh edited their review of gene: PROM1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 PKD1L3 Sarah Leigh edited their review of gene: PKD1L3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 NUP88 Sarah Leigh edited their review of gene: NUP88: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 MLKL Sarah Leigh edited their review of gene: MLKL: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 MIS12 Sarah Leigh edited their review of gene: MIS12: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 LDB2 Sarah Leigh edited their review of gene: LDB2: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 KARS Sarah Leigh edited their review of gene: KARS: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 HYDIN Sarah Leigh edited their review of gene: HYDIN: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 CC2D2A Sarah Leigh edited their review of gene: CC2D2A: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 BCAR1 Sarah Leigh edited their review of gene: BCAR1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.331 TMPRSS2 Catherine Snow Mode of inheritance for gene: TMPRSS2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.330 CD14 Catherine Snow Mode of inheritance for gene: CD14 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.329 CASP3 Catherine Snow Mode of inheritance for gene: CASP3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.328 BLK Catherine Snow Mode of inheritance for gene: BLK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.327 BLK Catherine Snow edited their review of gene: BLK: Changed mode of inheritance: Unknown
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence (PMID:31735293). Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Classified gene: TMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Gene: tmx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.68 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy
Early onset or syndromic epilepsy v2.67 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures
Early onset or syndromic epilepsy v2.66 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Intellectual disability v3.73 CXorf56 Rebecca Foulger changed review comment from: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.; to: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 noting X-linked inactivation in the comments. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier. Have set MOI to XLD for now, to capture affected females and males.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Classified gene: CXorf56 as Green List (high evidence)
Intellectual disability v3.73 CXorf56 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel by Konstantinos Varvagiannis, with a subsequent Green review by Zornitza Stark. Sufficient cases in PMIDs:29374277 and 31822863. The reported pattern of X-inactivation differs between the papers, but sufficient cases and relevant phenotype for inclusion on the panel.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Gene: cxorf56 has been classified as Green List (High Evidence).
Intellectual disability v3.72 CXorf56 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.
Intellectual disability v3.72 CXorf56 Rebecca Foulger Mode of inheritance for gene: CXorf56 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56: PMID:31822863. Rocha et al., 2019 report on 9 affected individuals (3 unrelated families) with mild to severe ID and variants in CXorf56. In comparison to PMID:29374277, X-linked skewing was seen in both affected females and the unaffected carrier had complete inactivation of the carrier X-chromosome.
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56
Intellectual disability v3.71 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Intellectual disability v3.71 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (DD seen in all patients in PMID:31820119) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Intellectual disability v3.71 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Intellectual disability v3.70 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Intellectual disability v3.68 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.64 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger Tag for-review tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger commented on gene: TRPM3: Excluding the individual harbouring a VUS, 7 individuals from PMID:31278393 (Dyment et al 2019) had the same de novo heterozygous variant in TRPM3 (p.Val837Met). This paper was considered when previously reviewed by GLHs. An Amber rating was chosen because public databases confirm that heterozygous loss-of-function variants of TRPM3 are observed in the general population (heterozygous gnomAD truncating variants occur in 18 of 25 canonical coding exons) and therefore the authors reasoned that simple haploinsufficiency was unlikely to be the mechanism of disease in their cohort. Therefore added 'for-review' tag, for reassesment at next GLH review.
COVID-19 research v0.327 APOE Eleanor Williams changed review comment from: PMID: 32451547 - Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. (Originially added to the panel as preprint: https://doi.org/10.1101/2020.05.07.20094409)
Sources: Literature; to: PMID: 32451547 - Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE e4e4 homozygotes were more likely to be COVID-19 test positives compared to e3e3 homozygotes. ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. (Originially added to the panel as preprint: https://doi.org/10.1101/2020.05.07.20094409)
Sources: Literature
COVID-19 research v0.327 APOE Eleanor Williams Publications for gene: APOE were set to https://doi.org/10.1101/2020.05.07.20094409
COVID-19 research v0.326 APOE Eleanor Williams changed review comment from: Preprint: https://doi.org/10.1101/2020.05.07.20094409 Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes.
ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the
excess incidence of COVID-19 in Blacks.
Sources: Literature; to: PMID: 32451547 - Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. (Originially added to the panel as preprint: https://doi.org/10.1101/2020.05.07.20094409)
Sources: Literature
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Classified gene: TUBA8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now, following Zornitza Stark's recent (Jan 2020) review. Additional case in PMID:31481326 (2020) but 2 Pakistani families (4 patients) previously reported may be related so remains a borderline case.
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.62 TUBA8 Rebecca Foulger commented on gene: TUBA8: Reviewing 2020 review comment by Zornitza noting additional publication: PMID:31481326. PMID:31481326. Lee et al., 2020 used targeted gene sequencing to identify malformations of cortical development in 81 patients. A homozygous TUBA8 p.Asn356ProfsTer63 variant was identified in one patient with 'Polymicrogyria, agenesis of CC, ventriculomegaly'. All patients had a confirmed diagnosis of epilepsy or DD.
COVID-19 research v0.326 ABO Catherine Snow Mode of inheritance for gene: ABO was changed from Other to Unknown
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (MIM:618744) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.61 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; seizures
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger commented on gene: WDR45B: Added 'for-review' tag based on Zornitza's Green review on a gene where an Amber rating was decided at the last GLH review. Of the publications listed, PMID:28503735 (Suleiman et al) report 3 families (2 with seizures). PMID:21937992. Najmabadi et al 2011 identify WDR45B (WDR45L) as a candidate gene for ID. PMID:27431290 (Anazi et al., 2017) identified likely pathogenic alleles in WDR45B in ID individuals. Little information provided about WDR45B phenotype.
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Tag for-review tag was added to gene: WDR45B.
CAKUT v1.151 RPGRIP1L Sarah Leigh changed review comment from: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.; to: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies and therefore not appropriate for the CAKUT panel. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.
CAKUT v1.151 RRM2B Sarah Leigh Classified gene: RRM2B as Red List (low evidence)
CAKUT v1.151 RRM2B Sarah Leigh Added comment: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RRM2B variants are metabolic renal disease / renal tubulopathy. RRM2B is green on Mitochondrial disorders (https://panelapp.genomicsengland.co.uk/panels/112/gene/RRM2B/) and Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/RRM2B/) panels.
CAKUT v1.151 RRM2B Sarah Leigh Gene: rrm2b has been classified as Red List (Low Evidence).
Intellectual disability v3.67 WDR45B Rebecca Foulger Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977
Intellectual disability v3.67 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
CAKUT v1.150 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537; 16799922; 15146186; 15146185; 15318302
CAKUT v1.149 NIPBL Sarah Leigh Classified gene: NIPBL as Green List (high evidence)
CAKUT v1.149 NIPBL Sarah Leigh Gene: nipbl has been classified as Green List (High Evidence).
CAKUT v1.148 NIPBL Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported, however, there seems to be little evidence of renal involvement.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported. PMID 8291540 presents extensive evidence for renal involvement in 61 Cornelia de Lange syndrome 1 cases; including structural anomalies of the kidney system in 25 (41%): absent or poor corticomedullary differentiation (8 cases), pelvic dilation (6 cases), vesicoureteral reflux (5 cases), small kidney (3 cases), isolated renal cyst (3 cases), renal ectopia (2 cases), renal function reduced (9 cases).
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Classified gene: ANKRD11 as Green List (high evidence)
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Added comment: Comment on list classification: Added to panel and reviewed Green by Tracy Lester. Although KBG syndrome has variable symptoms, epilepsy can be amongst the phenotypes. Based on literature review and Tracy Lester's review, updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Gene: ankrd11 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:27900361. Kleyner et al., 2016 describe a 13 yr old male with phenotypes including epilepsy, severe DD, distinct facial features and hand anomalies. Exome sequencing identified a novel de novo heterozygous LOF single bp duplication (c.6015dupA) in ANKRD11, leading to a premature stop codon.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:25543316. Samanta et al., 2015 report a 7 yr old boy with a ANKRD11 variant and developmental delay, focal epilepsy and behavioral concerns. He had frequent focal seizures but had enjoyed seizure-free state intermittently up to 9 months. He also had rare secondarily generalized tonic–clonic seizures, less than one episode in a year. After normal EEGs age 1 and 3, an EEG age 5 revealed EEG abnormalities.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger Publications for gene: ANKRD11 were set to 29565525
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger commented on gene: ANKRD11
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger Phenotypes for gene: ANKRD11 were changed from KBG syndrome to KBG syndrome, 148050
CAKUT v1.148 RPGRIP1L Sarah Leigh Classified gene: RPGRIP1L as Red List (low evidence)
CAKUT v1.148 RPGRIP1L Sarah Leigh Added comment: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.
CAKUT v1.148 RPGRIP1L Sarah Leigh Gene: rpgrip1l has been classified as Red List (Low Evidence).
COVID-19 research v0.325 SLAMF6 Catherine Snow gene: SLAMF6 was added
gene: SLAMF6 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLAMF6 was set to Unknown
Publications for gene: SLAMF6 were set to 30366106
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SLAMF6.

Natural cytotoxicity receptors, such as NKp46, NKp44, and NKp30 (NCR3), are selectively expressed on NK cells and cooperate in the induction of NK cell activity

Yigit et al (2019) summarised research in "SLAMF6 in health and disease: Implications for therapeutic targeting"
Sources: Expert list
COVID-19 research v0.324 SIGIRR Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SIGIRR.

Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection
Sources: Expert list; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SIGIRR.

Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection

Li et al. (2019) who worked with mice. Found that stabilization of Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation.
Sources: Expert list
COVID-19 research v0.324 SIGIRR Catherine Snow Publications for gene: SIGIRR were set to 29072292
COVID-19 research v0.323 SIGIRR Catherine Snow gene: SIGIRR was added
gene: SIGIRR was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SIGIRR was set to Unknown
Publications for gene: SIGIRR were set to 29072292
Review for gene: SIGIRR was set to RED
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SIGIRR.

Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection
Sources: Expert list
COVID-19 research v0.322 SLC11A1 Catherine Snow gene: SLC11A1 was added
gene: SLC11A1 was added to COVID-19 research. Sources: Literature,Expert list
Mode of inheritance for gene: SLC11A1 was set to Unknown
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SLC11A1

Multiple association studies with TB only, no viral associations
Sources: Literature, Expert list
DDG2P v2.8 KMT2E Rebecca Foulger Added comment: Comment on phenotypes: Removed MIM ID 616579 from phenotype field, as MIM:616579 is associated with a different gene (CHAMP1).
DDG2P v2.8 KMT2E Rebecca Foulger Phenotypes for gene: KMT2E were changed from INTELLECTUAL DISABILITY 616579; Neurodevelopmental disorder and Epilepsy 618512 to INTELLECTUAL DISABILITY; Neurodevelopmental disorder and Epilepsy 618512
DDG2P v2.7 GNAI1 Rebecca Foulger Publications for gene: GNAI1 were set to
DDG2P v2.6 CNOT3 Rebecca Foulger Publications for gene: CNOT3 were set to
COVID-19 research v0.321 SLC2A1 Ivone Leong Classified gene: SLC2A1 as Amber List (moderate evidence)
COVID-19 research v0.321 SLC2A1 Ivone Leong Gene: slc2a1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.320 SLC2A1 Ivone Leong gene: SLC2A1 was added
gene: SLC2A1 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLC2A1 was set to Unknown
Publications for gene: SLC2A1 were set to 15767416; 22308487
Review for gene: SLC2A1 was set to AMBER
Added comment: GLUT1 is a receptor for HTLV and suggested that perturbations in glucose metabolism resulting from interactions of HTLV envelope glycoproteins with GLUT1 are likely to contribute to HTLV-associated disorders (PMID: 15767416).

PMID: 22308487 shows that IL-7 induced upregulation of Glut1 changes glucos uptake and causes T lymphocyptes susceptible to HIV-1 infection.
Sources: Expert list
COVID-19 research v0.319 STAT6 Ivone Leong gene: STAT6 was added
gene: STAT6 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: STAT6 was set to Unknown
Publications for gene: STAT6 were set to 22000020; 21762972
Review for gene: STAT6 was set to RED
Added comment: Immune system gene: STAT6 mediates immune signaling in response to cytokines at the plasma membrane and to virus infection at the endoplasmic reticulum. Mice lacking Stat6 were susceptible to virus infection. Chen et al. (2011) (PMID: 22000020).

PMID: 21762972 found that STAT6 increases viral replication in the skin of patients with atopic dermatitis (chronic inflammatory skin disease) with a history of eczema herpeticum.
Sources: Expert list
COVID-19 research v0.318 TBX21 Ivone Leong Classified gene: TBX21 as Amber List (moderate evidence)
COVID-19 research v0.318 TBX21 Ivone Leong Gene: tbx21 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.317 TBX21 Ivone Leong gene: TBX21 was added
gene: TBX21 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: TBX21 was set to Unknown
Publications for gene: TBX21 were set to 15806396; 17378728; 19473434; 29399747
Phenotypes for gene: TBX21 were set to {Asthma, aspirin-induced, susceptibility to}, 208550; susceptibility to chronic HBV and HCV infection
Review for gene: TBX21 was set to AMBER
Added comment: TBX21 is a Th1-specific T-box transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (PMID: 15806396).

PMID: 17378728 found that variations at allele -1499 and haplotype D (--/AC) in the TBX21 promoter region contribute to susceptibility to HBV infection in the Chinese population.

PMID: 19473434 found that T-1993C polymorphism in the TBX21 promoter influences susceptibility to persistent HBV infection.

PMID: 29399747 found that rs4794067 (T-1993C) is significantly correlated with increased risk of HCV chronic infection (dominant model: OR = 5.690, 95% CI = 2.024-16.000) and susceptibility (dominant model: OR = 5.658, 95% CI = 2.514-12.735).
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ZNF34 Sarah Leigh reviewed gene: ZNF34: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ZFP36 Sarah Leigh reviewed gene: ZFP36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ZC3HC1 Sarah Leigh reviewed gene: ZC3HC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 TUBGCP3 Sarah Leigh reviewed gene: TUBGCP3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 TSPAN14 Sarah Leigh reviewed gene: TSPAN14: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 TNIP1 Sarah Leigh reviewed gene: TNIP1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 SLC13A4 Sarah Leigh reviewed gene: SLC13A4: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ODC1 Sarah Leigh reviewed gene: ODC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 MTPAP Sarah Leigh reviewed gene: MTPAP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 MICA Sarah Leigh reviewed gene: MICA: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 MED13L Sarah Leigh reviewed gene: MED13L: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 IVNS1ABP Sarah Leigh reviewed gene: IVNS1ABP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 FOXM1 Sarah Leigh reviewed gene: FOXM1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 FBRS Sarah Leigh reviewed gene: FBRS: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 CXorf36 Sarah Leigh reviewed gene: CXorf36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ABI3 Sarah Leigh reviewed gene: ABI3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.316 ZNF34 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ZFP36 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ZC3HC1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 TUBGCP3 Sarah Leigh Deleted their comment
COVID-19 research v0.316 TSPAN14 Sarah Leigh Deleted their comment
COVID-19 research v0.316 TNIP1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 SLC13A4 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ODC1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 MTPAP Sarah Leigh Deleted their comment
COVID-19 research v0.316 MICA Sarah Leigh Deleted their comment
COVID-19 research v0.316 MED13L Sarah Leigh Deleted their comment
COVID-19 research v0.316 IVNS1ABP Sarah Leigh Deleted their comment
COVID-19 research v0.316 FOXM1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 FBRS Sarah Leigh Deleted their comment
COVID-19 research v0.316 CXorf36 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ABI3 Sarah Leigh Deleted their comment
COVID-19 research v0.316 STK17B Ivone Leong gene: STK17B was added
gene: STK17B was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: STK17B was set to Unknown
Publications for gene: STK17B were set to 19017949; 19017948; 17364498; 17966037
Review for gene: STK17B was set to RED
Added comment: Drak2 -/- mice were susceptible to other models of autoimmunity and were normally resistant to acute viral infection.
Sources: Expert list
COVID-19 research v0.315 ZNF34 Sarah Leigh commented on gene: ZNF34: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 ZFP36 Sarah Leigh commented on gene: ZFP36: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 ZC3HC1 Sarah Leigh commented on gene: ZC3HC1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 TUBGCP3 Sarah Leigh commented on gene: TUBGCP3: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 TSPAN14 Sarah Leigh commented on gene: TSPAN14: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 TNIP1 Sarah Leigh commented on gene: TNIP1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 SLC13A4 Sarah Leigh commented on gene: SLC13A4: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 ODC1 Sarah Leigh commented on gene: ODC1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 MTPAP Sarah Leigh commented on gene: MTPAP: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 MICA Sarah Leigh commented on gene: MICA: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 MED13L Sarah Leigh commented on gene: MED13L: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 IVNS1ABP Sarah Leigh commented on gene: IVNS1ABP: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 FOXM1 Sarah Leigh commented on gene: FOXM1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 FBRS Sarah Leigh commented on gene: FBRS: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 CXorf36 Sarah Leigh commented on gene: CXorf36: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988). New gene name DIPK2B
COVID-19 research v0.315 ABI3 Sarah Leigh commented on gene: ABI3: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ZNF34 Sarah Leigh gene: ZNF34 was added
gene: ZNF34 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZNF34 was set to Unknown
Phenotypes for gene: ZNF34 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ZFP36 Sarah Leigh gene: ZFP36 was added
gene: ZFP36 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZFP36 was set to Unknown
Phenotypes for gene: ZFP36 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ZC3HC1 Sarah Leigh gene: ZC3HC1 was added
gene: ZC3HC1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZC3HC1 was set to Unknown
Phenotypes for gene: ZC3HC1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 TUBGCP3 Sarah Leigh gene: TUBGCP3 was added
gene: TUBGCP3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TUBGCP3 was set to Unknown
Phenotypes for gene: TUBGCP3 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 TSPAN14 Sarah Leigh gene: TSPAN14 was added
gene: TSPAN14 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TSPAN14 was set to Unknown
Phenotypes for gene: TSPAN14 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 TNIP1 Sarah Leigh gene: TNIP1 was added
gene: TNIP1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TNIP1 was set to Unknown
Phenotypes for gene: TNIP1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 SLC13A4 Sarah Leigh gene: SLC13A4 was added
gene: SLC13A4 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SLC13A4 was set to Unknown
Phenotypes for gene: SLC13A4 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ODC1 Sarah Leigh gene: ODC1 was added
gene: ODC1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ODC1 was set to Unknown
Phenotypes for gene: ODC1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 MTPAP Sarah Leigh gene: MTPAP was added
gene: MTPAP was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MTPAP was set to Unknown
Phenotypes for gene: MTPAP were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 MICA Sarah Leigh gene: MICA was added
gene: MICA was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MICA was set to Unknown
Phenotypes for gene: MICA were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 MED13L Sarah Leigh gene: MED13L was added
gene: MED13L was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MED13L was set to Unknown
Phenotypes for gene: MED13L were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 IVNS1ABP Sarah Leigh gene: IVNS1ABP was added
gene: IVNS1ABP was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IVNS1ABP was set to Unknown
Phenotypes for gene: IVNS1ABP were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 FOXM1 Sarah Leigh gene: FOXM1 was added
gene: FOXM1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FOXM1 was set to Unknown
Phenotypes for gene: FOXM1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 FBRS Sarah Leigh gene: FBRS was added
gene: FBRS was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FBRS was set to Unknown
Phenotypes for gene: FBRS were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 CXorf36 Sarah Leigh gene: CXorf36 was added
gene: CXorf36 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CXorf36 was set to Unknown
Phenotypes for gene: CXorf36 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ABI3 Sarah Leigh gene: ABI3 was added
gene: ABI3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ABI3 was set to Unknown
Phenotypes for gene: ABI3 were set to primary immunodeficiency
COVID-19 research v0.314 SLFN12L Ivone Leong gene: SLFN12L was added
gene: SLFN12L was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLFN12L was set to Unknown
Review for gene: SLFN12L was set to RED
Added comment: Mouse model-Immune system. Mice homozygous for the Slfn2 elektra mutation exhibited enhanced susceptibility to bacterial and viral infections and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. Slfn2 homologous to SFLN12 and SLFN12L
Sources: Expert list
COVID-19 research v0.313 SLFN12 Ivone Leong gene: SLFN12 was added
gene: SLFN12 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLFN12 was set to Unknown
Review for gene: SLFN12 was set to RED
Added comment: Mouse model-Immune system. Mice homozygous for the Slfn2 elektra mutation exhibited enhanced susceptibility to bacterial and viral infections and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. Slfn2 homologous to SFLN12 and SLFN12L
Sources: Expert list
COVID-19 research v0.312 SLC20A2 Ivone Leong gene: SLC20A2 was added
gene: SLC20A2 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLC20A2 was set to Unknown
Review for gene: SLC20A2 was set to RED
Added comment: GLVR2 is a receptor for amphotropic virus. Non-human viruses listed.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SOX6 Eleanor Williams Phenotypes for gene: SOX6 were changed from craniosynostosis; intellectual disability to craniosynostosis
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.8 SOX6 Eleanor Williams Phenotypes for gene: SOX6 were changed from to craniosynostosis; intellectual disability
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.7 SOX6 Eleanor Williams Publications for gene: SOX6 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams changed review comment from: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.; to: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams Added comment: Comment on mode of inheritance: All patients reported by Tolchin et al were heterozygous
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams Mode of inheritance for gene: SOX6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Classified gene: SOX6 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Added comment: Comment on list classification: 4 patients reported with genomic alterations affecting SOX6 are now reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Gene: sox6 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.4 SOX6 Eleanor Williams commented on gene: SOX6: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Respiratory ciliopathies including non-CF bronchiectasis v1.7 SPEF2 Zornitza Stark gene: SPEF2 was added
gene: SPEF2 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert list
Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344; 31942643
Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype
Review for gene: SPEF2 was set to AMBER
Added comment: 4 families reported with bi-allelic variants and sperm morphological abnormalities plus recurrent sinopulmonary infections and bronchiectasis, consistent with a PCD-like phenotype. Morphological abnormalities of the respiratory cilia were not observed. Mouse model recapitulated the infertility phenotype but also had hydrocephalus and sinusitis, again arguing for broader impact on ciliary function. Note other reports of individuals with bi-allelic variants and no respiratory phenotype reported. Given respiratory phenotype is milder and currently it is unclear in what proportion of individuals it is present, suggest Amber rating on this panel for now.
Sources: Expert list
Respiratory ciliopathies including non-CF bronchiectasis v1.7 TTC12 Zornitza Stark gene: TTC12 was added
gene: TTC12 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert list
Mode of inheritance for gene: TTC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC12 were set to 31978331
Phenotypes for gene: TTC12 were set to Ciliary dyskinesia
Review for gene: TTC12 was set to GREEN
gene: TTC12 was marked as current diagnostic
Added comment: Four unrelated families with LoF variants reported with a respiratory phenotype.
Sources: Expert list
Respiratory ciliopathies including non-CF bronchiectasis v1.7 RPGR Zornitza Stark reviewed gene: RPGR: Rating: GREEN; Mode of pathogenicity: None; Publications: 10094550, 12920075, 16055928; Phenotypes: Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, MIM# 300455; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Zornitza Stark reviewed gene: OFD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.7 DNAJB13 Zornitza Stark reviewed gene: DNAJB13: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486783; Phenotypes: Ciliary dyskinesia, primary, 34, MIM# 617091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.7 FOXJ1 Zornitza Stark reviewed gene: FOXJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630787; Phenotypes: Hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v1.7 NEK10 Zornitza Stark edited their review of gene: NEK10: Changed phenotypes: Ciliary dyskinesia, primary, 44, MIM# 618781; Set current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v1.7 NEK10 Zornitza Stark gene: NEK10 was added
gene: NEK10 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert list
Mode of inheritance for gene: NEK10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEK10 were set to 31959991
Phenotypes for gene: NEK10 were set to Ciliary dyskinesia, primary, 44, MIM# 618781
Review for gene: NEK10 was set to GREEN
Added comment: Nine individuals from 5 unrelated families, some functional data demonstrating hypoplastic or shorter cilia, and reduced overall ciliary motion compared to controls. No individuals had situs inversus but most had recurrent sinusitis and bronchiectasis.
Sources: Expert list
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP57 Zornitza Stark gene: CFAP57 was added
gene: CFAP57 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Other
Mode of inheritance for gene: CFAP57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP57 were set to bioRxiv 773028 doi: https://doi.org/10.1101/773028
Phenotypes for gene: CFAP57 were set to Primary ciliary dyskinesia
Review for gene: CFAP57 was set to RED
Added comment: Gene not in PubMed but recently published in bioRxiv in single patient with hom nonsense variants and Primary ciliary dyskinesia. Some functional data provided.
Sources: Other
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP54 Zornitza Stark edited their review of gene: CFAP54: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP54 Zornitza Stark reviewed gene: CFAP54: Rating: RED; Mode of pathogenicity: None; Publications: 26224312; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP46 Zornitza Stark reviewed gene: CFAP46: Rating: RED; Mode of pathogenicity: None; Publications: 29843777; Phenotypes: Heterotaxy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurological ciliopathies v1.7 ARL3 Zornitza Stark gene: ARL3 was added
gene: ARL3 was added to Neurological ciliopathies. Sources: Expert list
Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502
Phenotypes for gene: ARL3 were set to Joubert syndrome 35 MIM#61816
Review for gene: ARL3 was set to GREEN
gene: ARL3 was marked as current diagnostic
Added comment: 4 individuals from 2 unrelated consanguineous families with a phenotype resembling Joubert syndrome with homozygous missense mutations affecting the same residue (R149C, R149H), and supporting in vitro functional assays. An Arl3 null mouse model has a ciliary disease phenotype affecting the kidney, biliary tract, pancreas, and retina.
Sources: Expert list
Skeletal ciliopathies v1.3 PMM2 Zornitza Stark reviewed gene: PMM2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type Ia, MIM# 212065; Mode of inheritance: None
Skeletal ciliopathies v1.3 KIAA0586 Zornitza Stark gene: KIAA0586 was added
gene: KIAA0586 was added to Skeletal ciliopathies. Sources: Expert list
Mode of inheritance for gene: KIAA0586 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0586 were set to 26166481
Phenotypes for gene: KIAA0586 were set to Short-rib thoracic dysplasia 14 with polydactyly, MIM# 616546
Review for gene: KIAA0586 was set to AMBER
Added comment: Four unrelated families reported with a severe neurological/skeletal phenotype. However, note same variant identified in three of the families, indicative of founder effect. Gene is also associated with Joubert syndrome.
Sources: Expert list
Skeletal ciliopathies v1.3 CSPP1 Zornitza Stark gene: CSPP1 was added
gene: CSPP1 was added to Skeletal ciliopathies. Sources: Expert list
Mode of inheritance for gene: CSPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSPP1 were set to 24360808
Phenotypes for gene: CSPP1 were set to Joubert syndrome 21, MIM# 615636
Review for gene: CSPP1 was set to GREEN
gene: CSPP1 was marked as current diagnostic
Added comment: Classically associated with Joubert syndrome; however, note 4 individuals reported with features consistent with Jeune asphyxiating thoracic dystrophy, including short ribs, bell-shaped chest, and pulmonary hypoplasia.
Sources: Expert list
COVID-19 research v0.311 SERINC5 Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SERINC5

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection
Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SERINC5.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection
Sources: Literature
COVID-19 research v0.311 SERINC5 Catherine Snow Classified gene: SERINC5 as Amber List (moderate evidence)
COVID-19 research v0.311 SERINC5 Catherine Snow Gene: serinc5 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.310 SERINC5 Catherine Snow gene: SERINC5 was added
gene: SERINC5 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SERINC5 was set to Unknown
Publications for gene: SERINC5 were set to 26416734; 31918727
Review for gene: SERINC5 was set to AMBER
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SERINC5

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection
Sources: Literature
COVID-19 research v0.309 SERINC3 Catherine Snow Publications for gene: SERINC3 were set to
COVID-19 research v0.308 SERINC3 Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV)
Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3, inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sources: Literature
COVID-19 research v0.308 SERINC3 Catherine Snow Classified gene: SERINC3 as Amber List (moderate evidence)
COVID-19 research v0.308 SERINC3 Catherine Snow Gene: serinc3 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.307 SERINC3 Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.
Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV)
Sources: Literature
COVID-19 research v0.307 SERINC3 Catherine Snow gene: SERINC3 was added
gene: SERINC3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SERINC3 was set to Unknown
Review for gene: SERINC3 was set to AMBER
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.
Sources: Literature
COVID-19 research v0.306 SDC1 Catherine Snow gene: SDC1 was added
gene: SDC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SDC1 was set to Unknown
Publications for gene: SDC1 were set to 12530973
Review for gene: SDC1 was set to RED
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
NO gene disease association for SDC1. Bobardt et al. (2003) suggested that SDC-rich endothelial cells lining the vasculature can provide a microenvironment that boosts HIV replication in T cells.
Sources: Literature
COVID-19 research v0.305 SCN4A Catherine Snow changed review comment from: No further evidence since. Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
Sources: Literature; to: No further evidence reported since. Matthews et al. (2011) PMID 21220685 reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
Sources: Literature
COVID-19 research v0.305 SCN4A Catherine Snow gene: SCN4A was added
gene: SCN4A was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SCN4A was set to Unknown
Publications for gene: SCN4A were set to 21220685
Review for gene: SCN4A was set to RED
Added comment: No further evidence since. Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
Sources: Literature
COVID-19 research v0.304 TMPRSS2 Eleanor Williams reviewed gene: TMPRSS2: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.15.098616; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.304 SLC6A19 Eleanor Williams gene: SLC6A19 was added
gene: SLC6A19 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SLC6A19 was set to Unknown
Added comment: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients.
Sources: Literature
COVID-19 research v0.303 ACE2 Eleanor Williams changed review comment from: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural
Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.; to: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.
COVID-19 research v0.303 ACE2 Eleanor Williams edited their review of gene: ACE2: Added comment: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural
Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.; Changed publications: 32015507, https://doi.org/10.1101/2020.05.15.098616
COVID-19 research v0.303 TMPRSS4 Eleanor Williams gene: TMPRSS4 was added
gene: TMPRSS4 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TMPRSS4 was set to Unknown
Publications for gene: TMPRSS4 were set to https://doi.org/10.1101/2020.05.12.091314
Added comment: Preprint: Wruck and Adjaye https://doi.org/10.1101/2020.05.12.091314 - describe a meta-analysis focussing on the transcriptome data from human lung epithelial cells including samples infected with SARS-CoV-2 from a study described by Blanco Melo et al.12. The exploration was directed to co-expression with the known CoV-2 receptor ACE2. 72 genes significantly co-expressed with ACE2. Of the transmembrane serine proteases, the most significantly coexpressed with ACE2 was TMPRSS4, suggesting it to be a putative druggable target.
Pathway analysis revealed papilloma virus infection amongst the most significantly correlated pathways.
Sources: Literature
COVID-19 research v0.302 MBL2 Eleanor Williams commented on gene: MBL2
COVID-19 research v0.302 OAS1 Eleanor Williams reviewed gene: OAS1: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.13.093690; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.302 TMPRSS11A Eleanor Williams gene: TMPRSS11A was added
gene: TMPRSS11A was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TMPRSS11A was set to Unknown
Publications for gene: TMPRSS11A were set to https://doi.org/10.1101/2020.05.13.093690
Review for gene: TMPRSS11A was set to RED
Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found 2 rare variants p.Lys48Arg and p.Arg328Gln. For both of these variants, PolyPhen-2, SIFT and MutPred2
algorithms predict benign/tolerated effect but the protein structure of TMPRSS11a is not well known.
Sources: Literature
COVID-19 research v0.301 PRSS1 Eleanor Williams gene: PRSS1 was added
gene: PRSS1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PRSS1 was set to Unknown
Publications for gene: PRSS1 were set to https://doi.org/10.1101/2020.05.13.093690
Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found two rare variants in the PRSS1 gene, c.592-8C>T and p.Asn54Lys. Variant c.592-8C>T was previously detected
in patients with cystic fibrosis presenting with chronic pancreatitis and p.Asn54Lys is predicted to be possibly damaging.
Sources: Literature
COVID-19 research v0.300 PLG Eleanor Williams gene: PLG was added
gene: PLG was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PLG was set to Unknown
Publications for gene: PLG were set to https://doi.org/10.1101/2020.05.13.093690
Review for gene: PLG was set to RED
Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found 6 rare variants in PLG. p.Arg261His and p.Ala494Val are predicted to be probably damaging/deleterious.
Sources: Literature
COVID-19 research v0.299 FURIN Eleanor Williams commented on gene: FURIN: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found two rare variants in FURIN p.Thr33Ala and p.Gly146Ser. p.Gly146Ser. is predicted to be deleterious and may change its ability
to cleave furin-like sites in the S protein of the SARS-CoV-2.
COVID-19 research v0.299 ACE2 Eleanor Williams changed review comment from: Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-
RBD complexes of different species allowing us to anticipate the effects of amino acid sequence
variation of ACE2 on viral entry; to: Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-RBD complexes of different species allowing us to anticipate the effects of amino acid sequence variation of ACE2 on viral entry
COVID-19 research v0.299 ACE2 Eleanor Williams commented on gene: ACE2: Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-
RBD complexes of different species allowing us to anticipate the effects of amino acid sequence
variation of ACE2 on viral entry
COVID-19 research v0.299 MUC5B Eleanor Williams edited their review of gene: MUC5B: Changed publications: https://doi.org/10.1101/2020.05.12.20099333
COVID-19 research v0.299 MUC5B Eleanor Williams gene: MUC5B was added
gene: MUC5B was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MUC5B was set to Unknown
Review for gene: MUC5B was set to RED
Added comment: Preprint: van Moorsel et al https://doi.org/10.1101/2020.05.12.20099333 The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. They compared patients with severe COVID-19 to controls and found the MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for idiopathic pulmonary fibrosis (IPF) is protective against the development of severe COVID-19 disease.
Sources: Literature
Anophthalmia or microphthalmia v1.23 FAT1 Zornitza Stark gene: FAT1 was added
gene: FAT1 was added to Anophthalmia or microphthalmia. Sources: Expert list
Mode of inheritance for gene: FAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT1 were set to 30862798; 26905694
Phenotypes for gene: FAT1 were set to facial dysmorphism; colobomatous microphthalmia; ptosis; syndactyly with or without nephropathy
Review for gene: FAT1 was set to GREEN
gene: FAT1 was marked as current diagnostic
Added comment: 5 families reported with eye abnormalities in addition to the renal phenotype.
Sources: Expert list
Early onset or syndromic epilepsy v2.56 ANKRD11 Tracy Lester gene: ANKRD11 was added
gene: ANKRD11 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: ANKRD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD11 were set to 29565525
Phenotypes for gene: ANKRD11 were set to KBG syndrome
Penetrance for gene: ANKRD11 were set to Complete
Review for gene: ANKRD11 was set to GREEN
Added comment: KBG syndrome - EEG abnormalities, with or without seizures, have been reported in about 50% of affected individuals [Skjei et al 2007]. Age of onset can range from infancy to the teenage years [Low et al 2016]. The type of epilepsy is variable. Although tonic-clonic seizures are most common, no one specific type of epilepsy has been associated with the syndrome. Treatment with antiepileptic medication has proven effective in the majority of affected individuals. Many have remission of symptoms after adolescence [Lo-Castro et al 2013]. A few affected individuals have reportedly had severe seizures at a young age (described as infantile spasms / epileptic encephalopathy), in some cases drug resistant [C Ockeloen, personal communication; Samanta & Willis 2015]. - taken from GeneReviews, KBG syndrome, last updated Mar2018.
Penetrance of KBG syndrome is thought to be complete, but with variable expressivity.
Also associated with 16q24.3 deletions.
Sources: Expert Review
COVID-19 research v0.298 ACE2 Eleanor Williams commented on gene: ACE2: Preprint: https://doi.org/10.1101/2020.05.12.20098160 - Shovlin and Vizcaychip - variants in 213,158 exomes/genomes were integrated for ACE2 . ACMG/AMP-based pathogenicity criteria were applied. Modelling the ″COVID-resistant ″ state where pathogenic alleles would be beneficial, nine null alleles met PVS1. Thirty-seven variants met PM1 based on critical location +/-PP3 based on computational modelling. Modelling a ″COVID-susceptible ″ state, 31 variants in four upstream open reading frames and 5′ untranslated regions could meet PM1, and may have differential effects if aminoglycoside antibiotics were prescribed for pneumonia and sepsis.
COVID-19 research v0.298 SCARB1 Eleanor Williams Classified gene: SCARB1 as Amber List (moderate evidence)
COVID-19 research v0.298 SCARB1 Eleanor Williams Added comment: Comment on list classification: Rating Amber as there is some evidence that variants in this gene are associated with response to Hepatitus C virus
COVID-19 research v0.298 SCARB1 Eleanor Williams Gene: scarb1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.297 SCARB1 Eleanor Williams edited their review of gene: SCARB1: Changed publications: 12356718, 28827115, 29715527
COVID-19 research v0.297 SCARB1 Eleanor Williams gene: SCARB1 was added
gene: SCARB1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SCARB1 was set to Unknown
Added comment: Not associated with any relevant disease phenotype in OMIM. SCARB1 is also known as SRB1

PMID: 12356718 - Scarselli et al 2002 - Characterization of hepatitis C virus (HCV) envelope glycoprotein E2 binding after chemical or enzymic modification of the cell surface led to the identification of the scavenger receptor type B class I (SR-BI) as the E2 receptor on HepG2 cells.

PMID: 28827115 - Sadeghi et al 2017 - SCARB1 rs10846744 (CC) genotype (P=0.001) was strongly associated with sustained virological response

PMID: 28363797 - Westhaus et al 2018 - Non-synonymous variants: S112F and T175A have greatly reduced Hepatitus C virus (HCV) receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load.

PMID: 29715527 - Naffari et al 2018 -looked at treatment responses in 395 treatment-naïve patients with chronic Hepatitus C Virus (CHC) genotype 1 treated with pegylated interferon-α and ribavirin. Rapid virologic response (RVR), complete early virologic response (cEVR) , and sustained virologic responseSVR were significantly associated with SCARB1 rs10846744 (CC).
Sources: Literature
COVID-19 research v0.296 PYCARD Eleanor Williams gene: PYCARD was added
gene: PYCARD was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PYCARD was set to Unknown
Publications for gene: PYCARD were set to 18288107
Review for gene: PYCARD was set to RED
Added comment: Not associated with a disease phenotype in OMIM.

PYCARD is also known as ASC

PMID: 18288107 Muruve et al. 2008 - internalized adenoviral DNA induces maturation of pro-IL1B in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles.
Sources: Literature
COVID-19 research v0.295 PQBP1 Eleanor Williams gene: PQBP1 was added
gene: PQBP1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PQBP1 was set to Unknown
Publications for gene: PQBP1 were set to 26046437
Review for gene: PQBP1 was set to RED
Added comment: Not associated with a viral susceptibility phenotype in OMIM.

PMID: 26046437 - Yoh et al 2015 - found PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response
Sources: Literature
COVID-19 research v0.294 OCLN Eleanor Williams gene: OCLN was added
gene: OCLN was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: OCLN was set to Unknown
Publications for gene: OCLN were set to 19182773; 31328852
Review for gene: OCLN was set to RED
Added comment: Not associated with any viral susceptibility phenotypes in OMIM.

Evidence that OCLN is involved in HCV cell entry

PMID: 19182773 - Ploss et al 2009 - show that human occludin is an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp. Similarly, OCLN is required for the HCV-susceptibility of human cells, because its overexpression in uninfectable cells specifically enhanced HCVpp uptake, whereas its silencing in permissive cells impaired both HCVpp and HCVcc infection.

PMID: 31328852 - Lavie et al 2019 - looked at which residues in OCLN affect hepatitis C virus (HCV) entry. In the context of full-length OCLN, mutation of I279 and W281 residues only partially affected infection and cell surface localization.
Sources: Literature
COVID-19 research v0.293 NRP2 Eleanor Williams gene: NRP2 was added
gene: NRP2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: NRP2 was set to Unknown
Publications for gene: NRP2 were set to 30057110; 29120745
Review for gene: NRP2 was set to RED
Added comment: Not associated with a disease phenotype in OMIM or Gene2Phenotype.

PMID: 30057110: Martinez-Martin et al. (2018) identified NRP2 as a host receptor for human cytomegalovirus (HCMV) pentamer.

PMID: 29120745 -Raaben et al 2017 - A genome-wide haploid genetic screen identified the transmembrane protein neuropilin 2 (NRP2) and tetraspanin CD63 as factors for Lujo virus (LUJV) glycoprotein-mediated infection. Overexpression of NRP2 or its N-terminal domain enhances VSV-LUJV infection, and cells lacking NRP2 are deficient in wild-type LUJV infection.
Sources: Literature
COVID-19 research v0.292 NCR3 Eleanor Williams gene: NCR3 was added
gene: NCR3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: NCR3 was set to Unknown
Publications for gene: NCR3 were set to 26094914; 24845613; 30325780
Phenotypes for gene: NCR3 were set to {Malaria, mild, susceptibility to}, 609148
Review for gene: NCR3 was set to RED
Added comment: Associated with {Malaria, mild, susceptibility to} #609148 in OMIM. It is also known as NKp30.

Evidence that level of NCR3/NKp30 expression is reduced in those infected with virus, and increased in those who remain uninfected. No reports that SNVs in the NCR3 gene affect suceptibility to viral infection.

PMID: 26094914 - Mantovani et al 2015 - six different splice variants of the NKp30-encoding gene NCR3, which are known to be expressed on the cell surface. NKp30 receptor expression on NK cells and all isoforms were reduced in chronic hepatitis C virus(HCV)-infected patients.

PMID: 24845613 - Sugden et al 2014 - enhanced expression of NKp30 on NK cells resulted in protection from developing HCV infection in multiply exposed uninfected individuals

PMID: 30325780 - Lucar et al 2019 - report in HIV-2 patients a very significant reduced expression of the activating NKp30 receptor on NK cells.
Sources: Literature
COVID-19 research v0.291 MYH9 Eleanor Williams commented on gene: MYH9: Not associated with any relevant phenotypes in OMIM.
COVID-19 research v0.291 MYH9 Eleanor Williams edited their review of gene: MYH9: Changed rating: RED
COVID-19 research v0.291 MYH9 Eleanor Williams gene: MYH9 was added
gene: MYH9 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MYH9 was set to Unknown
Publications for gene: MYH9 were set to 20944748; 27112594; 31649651; 29879459
Review for gene: MYH9 was set to AMBER
Added comment: PMID: 20944748 - Arii et al. (2010) showed that nonmuscle myosin heavy chain IIA (NMHC-IIA), a subunit of nonmuscle myosin IIA (NM-IIA), functions as a herpes simplex virus-1 (HSV-1) entry receptor by interacting with glycoprotein B.

PMID: 27112594 - Gao et al (2016) report the identification of non-muscle myosin heavy chain 9 (MYH9) as an essential factor for PRRSV infection

Several other papers describing the role of MYH9 with porcine reproductive and respiratory syndrome virus invasion e.g. 31649651;29879459
Sources: Literature
COVID-19 research v0.290 MTOR Rebecca Foulger Classified gene: MTOR as Red List (low evidence)
COVID-19 research v0.290 MTOR Rebecca Foulger Added comment: Comment on list classification: A number of papers provide evidence that some viruses use mTOR signaling to promote their replication (e.g. PMID:28953980), and how inhibition of PI3K/TOR signaling inhibits viral replication (e.g. PMID:29475942). No variant studies on TOR so Red rating appropriate for now.
COVID-19 research v0.290 MTOR Rebecca Foulger Gene: mtor has been classified as Red List (Low Evidence).
COVID-19 research v0.289 MTOR Rebecca Foulger commented on gene: MTOR: PMID:19543266. Araki et al. (2009) demonstrated that mTOR is a major regulator of memory CD8 T-cell differentiation. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced the quantity and quality of virus-specific CD8 T cells. Rapamycin treatment also enhanced memory T-cell responses in nonhuman primates following vaccination with modified vaccinia virus Ankara.
COVID-19 research v0.289 MTOR Rebecca Foulger Phenotypes for gene: MTOR were changed from 19543266 to 19543266; 29475942; 28953980
COVID-19 research v0.288 MTOR Rebecca Foulger gene: MTOR was added
gene: MTOR was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MTOR was set to Unknown
Phenotypes for gene: MTOR were set to 19543266
Added comment: MTOR was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red. Notes from Julie Taylor and Alison Coffey (Illumina): mTOR is a major regulator of memory CD8 T-cell differentiation.
Sources: Other
COVID-19 research v0.287 MST1R Rebecca Foulger Classified gene: MST1R as Red List (low evidence)
COVID-19 research v0.287 MST1R Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red for now: Possible involvement in viral-induced carcinomas, but most evidence for a role in the viral life cycle comes from animal models.
COVID-19 research v0.287 MST1R Rebecca Foulger Gene: mst1r has been classified as Red List (Low Evidence).
COVID-19 research v0.286 MST1R Rebecca Foulger Added comment: Comment on publications: Note that in the literature, MST1R is often referred to as RON for the human and Stk for the rodent orthologs.
COVID-19 research v0.286 MST1R Rebecca Foulger Publications for gene: MST1R were set to 15557181; 22974584; 16527351
COVID-19 research v0.285 MST1R Rebecca Foulger commented on gene: MST1R: PMID:22974584 Chou et al., 2012 demonstrate involvement of MST1R (RON) in Epstein-Barr virus (EBV)-associated Nasopharyngeal carcinoma (NPC).
COVID-19 research v0.285 MST1R Rebecca Foulger commented on gene: MST1R: PMID:15557181. Lee et al. (2004) proposed that HIV-1 may directly or indirectly target MST1R (RON) to disrupt normal signals that actively suppress inflammation to assure a microenvironment favorable for virus replication.
COVID-19 research v0.285 MST1R Rebecca Foulger Publications for gene: MST1R were set to
COVID-19 research v0.284 MST1R Rebecca Foulger gene: MST1R was added
gene: MST1R was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MST1R was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MST1R were set to {Nasopharyngeal carcinoma, susceptibility to, 3}, 617075
Added comment: MST1R was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red.
Sources: Other
COVID-19 research v0.283 MRC1 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Amber. Functional data in PMID:12645947 shows role of MRC1 in binding HIV-1, and PMID:24969847 shows association of MRC1 SNP and sustained viral response to Hepatitis-C virus.; to: Comment on list classification: Updated rating from Red to Amber. Functional data in PMID:12645947 shows role of MRC1 in binding HIV-1, and PMID:24969847 shows association of MRC1 SNP and sustained viral response to Hepatitis-C virus. Papers also demonstrate variants are associated with susceptibility to other infectious diseases including leprosy (PMID:22392581) and pulmonary tuburculosis (PMID:23653008, 22393309).
COVID-19 research v0.283 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to 12645947; 24016730; 24969847
COVID-19 research v0.282 MRC1 Rebecca Foulger Classified gene: MRC1 as Amber List (moderate evidence)
COVID-19 research v0.282 MRC1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber. Functional data in PMID:12645947 shows role of MRC1 in binding HIV-1, and PMID:24969847 shows association of MRC1 SNP and sustained viral response to Hepatitis-C virus.
COVID-19 research v0.282 MRC1 Rebecca Foulger Gene: mrc1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.281 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to 12645947; 24016730
COVID-19 research v0.280 MRC1 Rebecca Foulger commented on gene: MRC1: PMID:24969847. Peng et al., 2014 evaluated whether polymorphisms of MRC-1 and IL-28B genes are associated with the treatment outcome of patients infected with hepatitis C (HCV). Among the MRC-1 SNPs, rs691005 was found to be associated with sustained viral responses (SVR) in HCV-1-infected patients.
COVID-19 research v0.280 MRC1 Rebecca Foulger changed review comment from: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Added to panel based on initial triage by Illumina (Tier 5 grouping) and additional curation. Notes from Julie Taylor and Alison Coffey (Illumina): One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Sources: Other; to: MRC1 was identified through an OMIM search for potential viral susceptibility genes. Added to panel based on initial triage by Illumina (Tier 5 grouping) and additional curation. Notes from Julie Taylor and Alison Coffey (Illumina): One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Sources: Other
COVID-19 research v0.280 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to 12645947
COVID-19 research v0.279 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to
COVID-19 research v0.278 MRC1 Rebecca Foulger commented on gene: MRC1: PMID:12645947. Nguyen and Hildreth (2003) showed that MRC1 (also called MMR) mediated the initial association of human immunodeficiency virus with macrophages lacking expression of DCSIGN, concluding that MRC1 (MMR) has a substantial role in binding and transmission of HIV-1 by macrophages.
CAKUT v1.147 ROR2 Sarah Leigh Added comment: Comment on mode of inheritance: Based on Gen2Phen confirmed rating of disease association including hydronephrosis in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
CAKUT v1.147 ROR2 Sarah Leigh Mode of inheritance for gene: ROR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.278 MRC1 Rebecca Foulger gene: MRC1 was added
gene: MRC1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MRC1 was set to Unknown
Added comment: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Added to panel based on initial triage by Illumina (Tier 5 grouping) and additional curation. Notes from Julie Taylor and Alison Coffey (Illumina): One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Sources: Other
CAKUT v1.146 ROR2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome recessive in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).; to: Comment on list classification: Associated with relevant phenotype in OMIM and as Confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome, autosomal recessive 268310 in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).

Green rating is based on Expert review by Zornitza Stark that ~10% of cases of Robinow syndrome, autosomal recessive 268310 have renal abnormalities and because of the Confirmed Gen2Phen rating.
COVID-19 research v0.277 MIF Rebecca Foulger changed review comment from: PMID:30944975. de Souza et al 2019 demonstrate in mince that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.; to: PMID:30944975. de Souza et al 2019 demonstrate in mice that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.
COVID-19 research v0.277 MIF Rebecca Foulger Classified gene: MIF as Amber List (moderate evidence)
COVID-19 research v0.277 MIF Rebecca Foulger Added comment: Comment on list classification: Upgraded rating from Red to Amber. Several animal models showing that MIF is expressed during viral infection (PMIDs:30944975, 31292300, 17909632) plus study of MIF polymorphisms and West Nile virus infection in PMID:26638028.
COVID-19 research v0.277 MIF Rebecca Foulger Gene: mif has been classified as Amber List (Moderate Evidence).
CAKUT v1.146 ROR2 Sarah Leigh Classified gene: ROR2 as Green List (high evidence)
CAKUT v1.146 ROR2 Sarah Leigh Gene: ror2 has been classified as Green List (High Evidence).
COVID-19 research v0.276 MIF Rebecca Foulger commented on gene: MIF: PMID:31292300. Smith et al., 2019 showed that, during influenza viral infection, Mif-deficient mice have less inflammation, viral load, and mortality compared with WT control mice.
COVID-19 research v0.276 MIF Rebecca Foulger commented on gene: MIF: PMID:26638028. Das et al., 2016 examined functional polymorphisms in MIF in a cohort of 454 North American patients with neuroinvasive West Nile virus (WNV) disease and found patients homozygous for high-expression MIF allels to be >20 fold more likely to have WNV encephalitis.
COVID-19 research v0.276 MIF Rebecca Foulger commented on gene: MIF: PMID:30944975. de Souza et al 2019 demonstrate in mince that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.
CAKUT v1.145 ROR2 Sarah Leigh Classified gene: ROR2 as Amber List (moderate evidence)
CAKUT v1.145 ROR2 Sarah Leigh Gene: ror2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.144 ROR2 Sarah Leigh Classified gene: ROR2 as Green List (high evidence)
CAKUT v1.144 ROR2 Sarah Leigh Gene: ror2 has been classified as Green List (High Evidence).
CAKUT v1.143 ROR2 Sarah Leigh Classified gene: ROR2 as Amber List (moderate evidence)
CAKUT v1.143 ROR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome recessive in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).
CAKUT v1.143 ROR2 Sarah Leigh Gene: ror2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.276 MIF Rebecca Foulger changed review comment from: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red. Notes from Julie Taylor and Alison Coffey (Illumina): Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to West Nile Virus lethality.; to: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping), added to panel initially as Red awaiting further curation. Notes from Julie Taylor and Alison Coffey (Illumina): Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to West Nile Virus lethality.
COVID-19 research v0.276 MIF Rebecca Foulger changed review comment from: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red.; to: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red. Notes from Julie Taylor and Alison Coffey (Illumina): Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to West Nile Virus lethality.
COVID-19 research v0.276 MIF Rebecca Foulger Classified gene: MIF as Red List (low evidence)
COVID-19 research v0.276 MIF Rebecca Foulger Added comment: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red.
COVID-19 research v0.276 MIF Rebecca Foulger Gene: mif has been classified as Red List (Low Evidence).
COVID-19 research v0.275 MIF Rebecca Foulger Phenotypes for gene: MIF were changed from to {Rheumatoid arthritis, systemic juvenile, susceptibility to}, 604302
COVID-19 research v0.274 MIF Rebecca Foulger gene: MIF was added
gene: MIF was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MIF was set to Unknown
Publications for gene: MIF were set to 17909632
Added comment: PMID:17909632. Arjona et al. (2007) showed that patients with acute West Nile virus (WNV) infection had increased levels of MIF in plasma and cerebrospinal fluid. Studies in mice showed that MIF is involved in WNV pathogenesis.
Sources: Other
COVID-19 research v0.273 MICA Rebecca Foulger Classified gene: MICA as Amber List (moderate evidence)
COVID-19 research v0.273 MICA Rebecca Foulger Added comment: Comment on list classification: MICA was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, upgraded rating from Red to Amber: A number of publications report association between MICA variants and HBV‐related hepatocellular carcinoma. Additional papers investigate MICA polymorphisms and response to viral infections/recovery (e.g. PMIDs:28925058, 15029237).
COVID-19 research v0.273 MICA Rebecca Foulger Gene: mica has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.272 MICA Rebecca Foulger Publications for gene: MICA were set to https://doi.org/10.1101/499988; 28925058; 31033131; 15029237
COVID-19 research v0.271 MICA Rebecca Foulger Publications for gene: MICA were set to https://doi.org/10.1101/499988; 28925058; 31033131
COVID-19 research v0.270 MICA Rebecca Foulger commented on gene: MICA: PMID:15029237. Karacki et al., 2004 investigated whether MICA polymorphisms are associated with HCV recovery. They compared the frequency of all known MICA polymorphisms in 2 large cohorts of people who recovered from either HCV or HBV infection and controls. Of the 27 unique MICA polymorphisms examined, only one was detected more often in persons who had cleared HCV infection, compared with controls: MICA*015. However <4% of all those examined with viral clearance were MICA*015 positive. They cannot exclude the possibility that MICA*015 is tightly linked to another allele that is responsible for the association.
CAKUT v1.142 ROR2 Sarah Leigh Publications for gene: ROR2 were set to
COVID-19 research v0.270 MICA Rebecca Foulger changed review comment from: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).; to: Several publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564,25270965).
COVID-19 research v0.270 MICA Rebecca Foulger commented on gene: MICA: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).
COVID-19 research v0.270 MICA Rebecca Foulger Phenotypes for gene: MICA were changed from to primary immunodeficiency
COVID-19 research v0.269 MICA Rebecca Foulger Publications for gene: MICA were set to
COVID-19 research v0.268 MICA Rebecca Foulger commented on gene: MICA: PMID:28925058. Luo et al., 2017 examined MICA/MIBC gene polymorphisms and respiratory syncytial virus (RSV) infection in 135 paediatric patients with and without pneuomina after RSV infection. Allele MICA*002:01/A9 and haplotype MICA*002:01-MICB*005:02 were negatively associated with RSV respiratory tract infections.
COVID-19 research v0.268 MICA Rebecca Foulger commented on gene: MICA
COVID-19 research v0.268 SLC1A5 Catherine Snow gene: SLC1A5 was added
gene: SLC1A5 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLC1A5 was set to Unknown
Review for gene: SLC1A5 was set to RED
Added comment: The SLC1A5 gene encodes a sodium-dependent neutral amino acid transporter that can act as a receptor for RD114/type D retrovirus, associated viruses are non-human
Sources: Expert list
Albinism or congenital nystagmus v1.5 BLOC1S6 Eleanor Williams Classified gene: BLOC1S6 as Green List (high evidence)
Albinism or congenital nystagmus v1.5 BLOC1S6 Eleanor Williams Added comment: Comment on list classification: Promoting from amber to red, as there are now 3 cases reported.
Albinism or congenital nystagmus v1.5 BLOC1S6 Eleanor Williams Gene: bloc1s6 has been classified as Green List (High Evidence).
Albinism or congenital nystagmus v1.4 BLOC1S6 Eleanor Williams Tag for-review tag was added to gene: BLOC1S6.
Albinism or congenital nystagmus v1.4 BLOC1S6 Eleanor Williams commented on gene: BLOC1S6
Renal ciliopathies v1.16 KIF14 Catherine Snow Classified gene: KIF14 as Amber List (moderate evidence)
Renal ciliopathies v1.16 KIF14 Catherine Snow Gene: kif14 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.267 LILRB1 Rebecca Foulger commented on gene: LILRB1: PMID:29528338. Davidson et al., 2018 tested whether LILRB1 genotype influences HCMV susceptibility by analysing LILRB1 genotypes (5 SNPs) in a group of 67 Canadian transplant patients. There was no association between LILRB1 SNPs and virus replication within the entire STCS population, but when the analyses were restricted to kidney transplant recipients, a significant association of rs10423364 was found with HCMV infection.
COVID-19 research v0.267 LILRB1 Rebecca Foulger commented on gene: LILRB1: PMID:32321755. Yu et al., 2020 studied a polymorphic 3-kb region within LILRB1 intron 1 that binds the transcription factor YY1 to regulate LILRB1 levels.
COVID-19 research v0.267 LILRB1 Rebecca Foulger commented on gene: LILRB1: PMID:30461037. Cadena-Mota et al., 2018 show that cytomegalovirus infection has a major effect on LILRB1 expression in NK and other mononuclear cells, and polymorphisms in the LILRB1 regulatory region appear to have a modulatory influence over this effect.
COVID-19 research v0.267 LILRB1 Rebecca Foulger Classified gene: LILRB1 as Amber List (moderate evidence)
COVID-19 research v0.267 LILRB1 Rebecca Foulger Added comment: Comment on list classification: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Amber. PMID:29528338 study investigates LILRB1 genotype and viral susceptibility and finds an association within transplant patients (but not within the population as a whole).
COVID-19 research v0.267 LILRB1 Rebecca Foulger Gene: lilrb1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.266 LILRB1 Rebecca Foulger commented on gene: LILRB1
COVID-19 research v0.266 LILRB1 Rebecca Foulger gene: LILRB1 was added
gene: LILRB1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: LILRB1 was set to Unknown
Publications for gene: LILRB1 were set to 30461037; 32321755; 29528338
Phenotypes for gene: LILRB1 were set to HCMV susceptibility
CAKUT v1.141 ROR2 Sarah Leigh Phenotypes for gene: ROR2 were changed from Robinow syndrome, autosomal recessive, MIM# 268310 to Robinow syndrome, autosomal recessive 268310
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Tag for-review tag was added to gene: BLOC1S6.
CAKUT v1.140 ROBO2 Sarah Leigh Classified gene: ROBO2 as Green List (high evidence)
CAKUT v1.140 ROBO2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 4 families, together with supportive mouse models.
CAKUT v1.140 ROBO2 Sarah Leigh Gene: robo2 has been classified as Green List (High Evidence).
CAKUT v1.139 ROBO2 Sarah Leigh Phenotypes for gene: ROBO2 were changed from Vesicoureteral reflux 2, 610878; Vesicoureteral Reflux to Vesicoureteral reflux 2 610878
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Classified gene: BLOC1S6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. The immune dysfunction phenotype is not as clear as the platelet anomalies and ocular / oculocutaneous albinism phenotype. Therefore rating this gene as amber for now.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Gene: bloc1s6 has been classified as Amber List (Moderate Evidence).
CAKUT v1.138 WNT5A Catherine Snow Classified gene: WNT5A as Amber List (moderate evidence)
CAKUT v1.138 WNT5A Catherine Snow Added comment: Comment on list classification: WNT5A associated with Robinow syndrome. Although renal disorder is associated with syndrome limited known variants reported in literature. Lots of functional models in mice therefore rating as Amber due to lack of human variants
CAKUT v1.138 WNT5A Catherine Snow Gene: wnt5a has been classified as Amber List (Moderate Evidence).
CAKUT v1.137 WNT5A Catherine Snow Publications for gene: WNT5A were set to 27002738; 31032853
CAKUT v1.137 WNT5A Catherine Snow Publications for gene: WNT5A were set to 27002738
CAKUT v1.136 WNT5A Catherine Snow Publications for gene: WNT5A were set to
COVID-19 research v0.265 KHDRBS1 Rebecca Foulger Classified gene: KHDRBS1 as Amber List (moderate evidence)
COVID-19 research v0.265 KHDRBS1 Rebecca Foulger Added comment: Comment on list classification: KHDRBS1 (SAM68) was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Amber. Functional evidence to suggest KHDRBS1 (SAM68) may serve as a proviral factor facilitate viral replication through interaction with the viral genome. A number of papers report interaction of KHDRBS1 (SAM68) and viral elements (e.g. PMIDs:26695943, 26202240, 27057671, 15701759) to positive regulate viral infection (although the viral processes affected differ between papers).
COVID-19 research v0.265 KHDRBS1 Rebecca Foulger Gene: khdrbs1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.264 KHDRBS1 Rebecca Foulger commented on gene: KHDRBS1: Notes from Julie Taylor and Alison Coffey (Illumina): KHDRBS1 belongs to the evolutionarily conserved signal transduction activator of RNA (STAR) family of RNA-binding proteins. These proteins play key roles during cell differentiation and development (summary by Bianchi et al., 2010). Cote et al. (2003, PMID:12529443) noted that KHDRBS1 (SAM68) can export unspliced human immunodeficiency virus (HIV) RNAs, and they found that treatment of cells with methylase inhibitors prevented the ability of KHDRBS1 (SAM68) to export unspliced HIV RNAs from transfected COS-7 cells.
COVID-19 research v0.264 KHDRBS1 Rebecca Foulger gene: KHDRBS1 was added
gene: KHDRBS1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: KHDRBS1 was set to Unknown
Publications for gene: KHDRBS1 were set to 12529443; 26695943; 26202240; 27057671; 15701759; 31068419
Added comment: PMID:31068419. Qin et al., 2019 report that KHDRBS1 (SAM68) promotes hepatitis C virus (HCV) replication without affecting viral translation. HCV infection triggers the translocation of the SAM68 protein from the nucleus to the cytoplasm, where it interacts with the HCV RNA genome.
Sources: Other
CAKUT v1.135 ROBO2 Sarah Leigh Publications for gene: ROBO2 were set to
COVID-19 research v0.263 HIVEP1 Rebecca Foulger Classified gene: HIVEP1 as Red List (low evidence)
COVID-19 research v0.263 HIVEP1 Rebecca Foulger Added comment: Comment on list classification: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red. Not yet associated with an OMIM disorder. No direct evidence for a role in viral infection, but binds a DNA sequence that is common in the enhancer elements of numerous viral promoters including simian virus 40, cytomegalovirus and HIV.
COVID-19 research v0.263 HIVEP1 Rebecca Foulger Gene: hivep1 has been classified as Red List (Low Evidence).
COVID-19 research v0.262 HIVEP1 Rebecca Foulger Added comment: Comment on publications: Note that PMID:24719322 (Modulation of TLR3, TLR4 and TLR7 Mediated IFN-β, Rantes and TNFα Production by HIVEP1) was withdrawn by the author.
COVID-19 research v0.262 HIVEP1 Rebecca Foulger Publications for gene: HIVEP1 were set to
CAKUT v1.134 NIPBL Sarah Leigh Classified gene: NIPBL as Amber List (moderate evidence)
CAKUT v1.134 NIPBL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported, however, there seems to be little evidence of renal involvement.
CAKUT v1.134 NIPBL Sarah Leigh Gene: nipbl has been classified as Amber List (Moderate Evidence).
CAKUT v1.133 TBC1D1 Catherine Snow Classified gene: TBC1D1 as Green List (high evidence)
CAKUT v1.133 TBC1D1 Catherine Snow Added comment: Comment on list classification: Functional work in mouse and one paper with four unrelated individuals with pedigree analysis show evidence for a role of TBC1D1 variants in CAKUT pathogenesis. Although only identified in PMID: 26572137 paper sufficient evidence to rate TBC1D1 as Green
CAKUT v1.133 TBC1D1 Catherine Snow Gene: tbc1d1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.172 BCL11B Eleanor Williams Classified gene: BCL11B as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.172 BCL11B Eleanor Williams Added comment: Comment on list classification: Following review by the Genomics England clinical team it was decided to promote this gene from red to amber pending further cases with an immune deficiency phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.172 BCL11B Eleanor Williams Gene: bcl11b has been classified as Amber List (Moderate Evidence).
CAKUT v1.132 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537; 16799922; 15146186; 15146185; 15318302
CAKUT v1.131 NIPBL Sarah Leigh Phenotypes for gene: NIPBL were changed from Cornelia de Lange syndrome 1, MIM# 122470 to Cornelia de Lange syndrome 1 122470
CAKUT v1.130 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537
CAKUT v1.129 VPS33B Catherine Snow Classified gene: VPS33B as Red List (low evidence)
CAKUT v1.129 VPS33B Catherine Snow Added comment: Comment on list classification: Downgraded following identification by expert review as VPS33B is a tubulopathy gene.
CAKUT v1.129 VPS33B Catherine Snow Gene: vps33b has been classified as Red List (Low Evidence).
CAKUT v1.128 STRA6 Catherine Snow Classified gene: STRA6 as Green List (high evidence)
CAKUT v1.128 STRA6 Catherine Snow Added comment: Comment on list classification: Sufficient number of unrelated cases identified in the literature to classify STRA6 Green for this panel
CAKUT v1.128 STRA6 Catherine Snow Gene: stra6 has been classified as Green List (High Evidence).
CAKUT v1.127 STRA6 Catherine Snow Publications for gene: STRA6 were set to 26373900; 17503335
CAKUT v1.127 STRA6 Catherine Snow Publications for gene: STRA6 were set to
CAKUT v1.126 SLIT2 Catherine Snow Classified gene: SLIT2 as Amber List (moderate evidence)
CAKUT v1.126 SLIT2 Catherine Snow Added comment: Comment on list classification: Gene identified as missing from panel by expert reviewer. Rating as Amber as gene disease only reported in PMID:26026792 no further evidence of this association and missing segregation information for some of the three individuals.
CAKUT v1.126 SLIT2 Catherine Snow Gene: slit2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.125 SLIT2 Catherine Snow Publications for gene: SLIT2 were set to
Paediatric disorders - additional genes v1.55 NADSYN1 Sarah Leigh Classified gene: NADSYN1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.55 NADSYN1 Sarah Leigh Gene: nadsyn1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.54 NADSYN1 Sarah Leigh Tag for-review tag was added to gene: NADSYN1.
Paediatric disorders - additional genes v1.54 NADSYN1 Sarah Leigh gene: NADSYN1 was added
gene: NADSYN1 was added to Paediatric disorders - additional genes. Sources: Expert list,Literature
Mode of inheritance for gene: NADSYN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NADSYN1 were set to 31883644
Phenotypes for gene: NADSYN1 were set to Vertebral, cardiac, renal, and limb defects syndrome 3 618845
Review for gene: NADSYN1 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families, together with supportive functional studies (PMID 31883644).
Sources: Expert list, Literature
CAKUT v1.124 NADSYN1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families, together with supportive functional studies (PMID 31883644).
COVID-19 research v0.261 HIVEP1 Rebecca Foulger commented on gene: HIVEP1
COVID-19 research v0.261 HIVEP1 Rebecca Foulger gene: HIVEP1 was added
gene: HIVEP1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: HIVEP1 was set to Unknown
CAKUT v1.124 NADSYN1 Sarah Leigh Phenotypes for gene: NADSYN1 were changed from Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral to Vertebral, cardiac, renal, and limb defects syndrome 3 618845
CAKUT v1.123 NADSYN1 Sarah Leigh Classified gene: NADSYN1 as Green List (high evidence)
CAKUT v1.123 NADSYN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families.
CAKUT v1.123 NADSYN1 Sarah Leigh Gene: nadsyn1 has been classified as Green List (High Evidence).
CAKUT v1.122 SALL4 Catherine Snow Classified gene: SALL4 as Amber List (moderate evidence)
CAKUT v1.122 SALL4 Catherine Snow Added comment: Comment on list classification: This gene has evidence of a gene phenotype relationship from one active group however since 2006 no further gene disease relationship has been reported. SALL4 recently associated with leukemic hematopoiesis. Therefore due to lack of recent association rating gene as Amber
CAKUT v1.122 SALL4 Catherine Snow Gene: sall4 has been classified as Amber List (Moderate Evidence).
CAKUT v1.121 SALL4 Catherine Snow Phenotypes for gene: SALL4 were changed from SALL4- related disorders to Duane-radial ray syndrome, 607323
Neurological ciliopathies v1.7 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Added comment: Four individuals from two unrelated families reported.; Changed rating: AMBER; Changed publications: 28749478, 27894351, 30327448; Changed phenotypes: hindbrain abnormalities, kidney and bone marrow abnormalities
Renal ciliopathies v1.15 DCDC2 Zornitza Stark edited their review of gene: DCDC2: Added comment: Two families with renal ciliopathy phenotype reported.

PMID: 25557784 - a single case (1 hom PTC) with nephronophthisis.

PMID: 31821705 - single report (1 hom PTC) with nephronophthisis with renal-hepatic ciliopathy with phenotypic characteristics that include hepatosplenomegaly, hepatic fibrosis with bile cholestasis, increased kidney echogenicity, and end-stage renal disease. MRI did not indicate cerebellar atrophy or MTS; Changed rating: AMBER; Changed publications: 25557784, 31821705; Changed phenotypes: Nephronophthisis 19, MIM#616217
Neurological ciliopathies v1.7 CCDC28B Zornitza Stark gene: CCDC28B was added
gene: CCDC28B was added to Neurological ciliopathies. Sources: Expert list
Mode of inheritance for gene: CCDC28B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC28B were set to 32139166
Phenotypes for gene: CCDC28B were set to Joubert syndrome
Review for gene: CCDC28B was set to AMBER
Added comment: Note new publication relating to this gene, which has previously been postulated to be a modifier for BBS. PMID: 32139166 - Single family with Joubert syndrome. Patient was homozygous for a missense, with polydactyly, severe ID, and the molar tooth sign observed in MRI. Sibling fetus MRI showed vermis hypoplasia, and was also homozygous for the variant. Parents confirmed unaffected carriers.

Borderline Amber/Red but note knockdown of CCDC28B in human TERT retinal pigment epithelial cells reduced both the number and length of cilia, providing some supportive evidence.
Sources: Expert list
Ophthalmological ciliopathies v1.4 C8orf37 Zornitza Stark reviewed gene: C8orf37: Rating: GREEN; Mode of pathogenicity: None; Publications: 27008867, 26854863, 22177090, 25113443, 2686542625802487; Phenotypes: Bardet-Biedl syndrome 21 617406, Cone-rod dystrophy 16 614500, Retinitis pigmentosa 64 614500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Renal ciliopathies v1.15 BBIP1 Zornitza Stark reviewed gene: BBIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24026985, 32055034; Phenotypes: Bardet-Biedl syndrome 18, MIM#615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-CF bronchiectasis v1.22 CCDC39 Catherine Snow Classified gene: CCDC39 as Red List (low evidence)
Non-CF bronchiectasis v1.22 CCDC39 Catherine Snow Gene: ccdc39 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.21 CCDC39 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.21 CCDC40 Catherine Snow Classified gene: CCDC40 as Red List (low evidence)
Non-CF bronchiectasis v1.21 CCDC40 Catherine Snow Gene: ccdc40 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.20 CCDC40 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.20 DNAAF1 Catherine Snow Classified gene: DNAAF1 as Red List (low evidence)
Non-CF bronchiectasis v1.20 DNAAF1 Catherine Snow Gene: dnaaf1 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.19 DNAAF1 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.19 DNAAF2 Catherine Snow Classified gene: DNAAF2 as Red List (low evidence)
Non-CF bronchiectasis v1.19 DNAAF2 Catherine Snow Gene: dnaaf2 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.18 DNAAF2 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.18 DNAH11 Catherine Snow Classified gene: DNAH11 as Red List (low evidence)
Non-CF bronchiectasis v1.18 DNAH11 Catherine Snow Gene: dnah11 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.17 DNAH11 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.17 DNAH5 Catherine Snow Classified gene: DNAH5 as Red List (low evidence)
Non-CF bronchiectasis v1.17 DNAH5 Catherine Snow Gene: dnah5 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.16 DNAH5 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.16 DNAI1 Catherine Snow Classified gene: DNAI1 as Red List (low evidence)
Non-CF bronchiectasis v1.16 DNAI1 Catherine Snow Gene: dnai1 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.15 DNAI1 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.15 DNAL1 Catherine Snow Classified gene: DNAL1 as Red List (low evidence)
Non-CF bronchiectasis v1.15 DNAL1 Catherine Snow Gene: dnal1 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.14 DNAL1 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.14 DNAI2 Catherine Snow Classified gene: DNAI2 as Red List (low evidence)
Non-CF bronchiectasis v1.14 DNAI2 Catherine Snow Gene: dnai2 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.13 DNAI2 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.13 DNAI2 Catherine Snow Deleted their comment
Non-CF bronchiectasis v1.13 DNAL1 Catherine Snow Classified gene: DNAL1 as Green List (high evidence)
Non-CF bronchiectasis v1.13 DNAL1 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.13 DNAL1 Catherine Snow Gene: dnal1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.12 DNAI2 Catherine Snow Classified gene: DNAI2 as Green List (high evidence)
Non-CF bronchiectasis v1.12 DNAI2 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.12 DNAI2 Catherine Snow Gene: dnai2 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.11 DNAI1 Catherine Snow Classified gene: DNAI1 as Green List (high evidence)
Non-CF bronchiectasis v1.11 DNAI1 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.11 DNAI1 Catherine Snow Gene: dnai1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.10 DNAH5 Catherine Snow Classified gene: DNAH5 as Green List (high evidence)
Non-CF bronchiectasis v1.10 DNAH5 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.10 DNAH5 Catherine Snow Gene: dnah5 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.9 DNAH11 Catherine Snow Classified gene: DNAH11 as Green List (high evidence)
Non-CF bronchiectasis v1.9 DNAH11 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.9 DNAH11 Catherine Snow Gene: dnah11 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.8 DNAAF2 Catherine Snow Classified gene: DNAAF2 as Green List (high evidence)
Non-CF bronchiectasis v1.8 DNAAF2 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.8 DNAAF2 Catherine Snow Gene: dnaaf2 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.7 DNAAF1 Catherine Snow Classified gene: DNAAF1 as Green List (high evidence)
Non-CF bronchiectasis v1.7 DNAAF1 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.7 DNAAF1 Catherine Snow Gene: dnaaf1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.6 CCDC40 Catherine Snow Classified gene: CCDC40 as Green List (high evidence)
Non-CF bronchiectasis v1.6 CCDC40 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.6 CCDC40 Catherine Snow Gene: ccdc40 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.5 CCDC39 Catherine Snow Classified gene: CCDC39 as Green List (high evidence)
Non-CF bronchiectasis v1.5 CCDC39 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.5 CCDC39 Catherine Snow Gene: ccdc39 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Deleted their comment
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Classified gene: MYOCD as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Added comment: Comment on list classification: Chirag Patel (Genetic Health Queensland)(16 Jan 2020) review on CAKUT panel: Four unrelated families. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease). Cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity.
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Gene: myocd has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Classified gene: MYOCD as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Added comment: Comment on list classification: Chirag Patel (Genetic Health Queensland)(16 Jan 2020) review on CAKUT panel: Four unrelated families. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease). Cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity.
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Gene: myocd has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.52 MYOCD Sarah Leigh Tag for-review tag was added to gene: MYOCD.
Paediatric disorders - additional genes v1.52 MYOCD Sarah Leigh gene: MYOCD was added
gene: MYOCD was added to Paediatric disorders - additional genes. Sources: Expert Review
Mode of inheritance for gene: MYOCD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYOCD were set to 31513549
Phenotypes for gene: MYOCD were set to Megabladder, congenital 618719
Review for gene: MYOCD was set to AMBER
Added comment: Sources: Expert Review
CAKUT v1.120 MYOCD Sarah Leigh Classified gene: MYOCD as Green List (high evidence)
CAKUT v1.120 MYOCD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
CAKUT v1.120 MYOCD Sarah Leigh Gene: myocd has been classified as Green List (High Evidence).
CAKUT v1.119 MYOCD Sarah Leigh Phenotypes for gene: MYOCD were changed from Megabladder; congenital heart disease; cardiomyopathy to Megabladder, congenital 618719
CAKUT v1.118 MYOCD Sarah Leigh Publications for gene: MYOCD were set to PMID: 31513549
CAKUT v1.117 NOTCH2 Sarah Leigh Classified gene: NOTCH2 as Green List (high evidence)
CAKUT v1.117 NOTCH2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 10 variants reported been reported in unrealated with features of Alagille syndrome (PMID 22209762).
CAKUT v1.117 NOTCH2 Sarah Leigh Gene: notch2 has been classified as Green List (High Evidence).
CAKUT v1.116 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to 22105858; 16773578
CAKUT v1.115 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to 22105858
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted from Green to Amber based on advice from the Genomics England Clinical Team. In email correspondence, Helen Brittain notes that this is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Zornitza's review on the Genetic Epilepsy Syndromes panel focuses on the differing ratings of ALKBH8 on the ID (Green) and Epilepsy (Amber) panels. Based on borderline evidence, I have demoted ALKBH8 to Amber on the ID panel to be consistent with the GLH consensus on the Epilepsy panel (R59 #402).
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
CAKUT v1.114 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to PMID: 22105858
CAKUT v1.113 NOTCH2 Sarah Leigh Added comment: Comment on phenotypes: Alagille syndrome 2 610205
CAKUT v1.113 NOTCH2 Sarah Leigh Phenotypes for gene: NOTCH2 were changed from Alagille syndrome 2; OMIM #610205 to Alagille syndrome 2 610205
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger Tag for-review tag was added to gene: ALKBH8.
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger commented on gene: ALKBH8: Kept rating as Amber following advice from the Genomics England Clinical Team since Amber was the GLH opinion. This is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Have added 'for-review' tag to highlight the Green review from Zornitza. Note that Zornitza's review focuses on the differing ratings of ALKBH8 on the ID and Epilepsy panels, which I will align for consistency: no new evidence in the review.
COVID-19 research v0.260 CXorf36 Sarah Leigh Tag new-gene-name tag was added to gene: CXorf36.
COVID-19 research v0.260 ZNF34 Sarah Leigh reviewed gene: ZNF34: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ZFP36 Sarah Leigh reviewed gene: ZFP36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ZC3HC1 Sarah Leigh reviewed gene: ZC3HC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 TUBGCP3 Sarah Leigh reviewed gene: TUBGCP3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 TSPAN14 Sarah Leigh reviewed gene: TSPAN14: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 TNIP1 Sarah Leigh reviewed gene: TNIP1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 SLC13A4 Sarah Leigh reviewed gene: SLC13A4: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ODC1 Sarah Leigh reviewed gene: ODC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 MTPAP Sarah Leigh reviewed gene: MTPAP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 MICA Sarah Leigh reviewed gene: MICA: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 MED13L Sarah Leigh reviewed gene: MED13L: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 IVNS1ABP Sarah Leigh reviewed gene: IVNS1ABP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 FOXM1 Sarah Leigh reviewed gene: FOXM1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 FBRS Sarah Leigh reviewed gene: FBRS: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 CXorf36 Sarah Leigh reviewed gene: CXorf36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ABI3 Sarah Leigh reviewed gene: ABI3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.259 ZNF34 Sarah Leigh gene: ZNF34 was added
gene: ZNF34 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ZNF34 was set to Unknown
COVID-19 research v0.258 ZFP36 Sarah Leigh gene: ZFP36 was added
gene: ZFP36 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ZFP36 was set to Unknown
COVID-19 research v0.257 ZC3HC1 Sarah Leigh gene: ZC3HC1 was added
gene: ZC3HC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ZC3HC1 was set to Unknown
COVID-19 research v0.256 TUBGCP3 Sarah Leigh gene: TUBGCP3 was added
gene: TUBGCP3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TUBGCP3 was set to Unknown
COVID-19 research v0.255 TSPAN14 Sarah Leigh gene: TSPAN14 was added
gene: TSPAN14 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TSPAN14 was set to Unknown
COVID-19 research v0.254 TNIP1 Sarah Leigh gene: TNIP1 was added
gene: TNIP1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TNIP1 was set to Unknown
COVID-19 research v0.253 SLC13A4 Sarah Leigh gene: SLC13A4 was added
gene: SLC13A4 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SLC13A4 was set to Unknown
COVID-19 research v0.252 ODC1 Sarah Leigh gene: ODC1 was added
gene: ODC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ODC1 was set to Unknown
COVID-19 research v0.251 MTPAP Sarah Leigh gene: MTPAP was added
gene: MTPAP was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MTPAP was set to Unknown
COVID-19 research v0.250 MICA Sarah Leigh gene: MICA was added
gene: MICA was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MICA was set to Unknown
COVID-19 research v0.249 MED13L Sarah Leigh gene: MED13L was added
gene: MED13L was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MED13L was set to Unknown
COVID-19 research v0.248 IVNS1ABP Sarah Leigh gene: IVNS1ABP was added
gene: IVNS1ABP was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: IVNS1ABP was set to Unknown
COVID-19 research v0.247 FOXM1 Sarah Leigh gene: FOXM1 was added
gene: FOXM1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: FOXM1 was set to Unknown
COVID-19 research v0.246 FBRS Sarah Leigh gene: FBRS was added
gene: FBRS was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: FBRS was set to Unknown
COVID-19 research v0.245 CXorf36 Sarah Leigh gene: CXorf36 was added
gene: CXorf36 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: CXorf36 was set to Unknown
COVID-19 research v0.244 ABI3 Sarah Leigh gene: ABI3 was added
gene: ABI3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ABI3 was set to Unknown
COVID-19 research v0.243 SOCS1 Sarah Leigh edited their review of gene: SOCS1: Changed publications: 12588885, 12588885, 18172216, https://doi.org/10.1101/499988
COVID-19 research v0.243 SOCS1 Sarah Leigh changed review comment from: PMID 12588885: In coxsackievirus-infected mice cardiac myocyte-specific transgenic expression of SOCS1 inhibited virus-induced signaling of JAK and STAT resulting in increased viral replication, cardiomyopathy, and mortality compared to controls. Inhibition of SOCS in cardiac myocytes increased myocyte resistance to the acute cardiac injury of enteroviral infection. It was suggested that inhibition of SOCS could augment the host-cell antiviral system and might prevent viral-mediated end-organ damage during the early stages of infection.
Sources: Literature; to: PMID 12588885: In coxsackievirus-infected mice cardiac myocyte-specific transgenic expression of SOCS1 inhibited virus-induced signaling of JAK and STAT resulting in increased viral replication, cardiomyopathy, and mortality compared to controls. Inhibition of SOCS in cardiac myocytes increased myocyte resistance to the acute cardiac injury of enteroviral infection. It was suggested that inhibition of SOCS could augment the host-cell antiviral system and might prevent viral-mediated end-organ damage during the early stages of infection.
https://doi.org/10.1101/499988 reports: Genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci).

Sources: Literature
COVID-19 research v0.243 SOCS1 Sarah Leigh gene: SOCS1 was added
gene: SOCS1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SOCS1 was set to Unknown
Publications for gene: SOCS1 were set to 12588885; 12588885; 18172216
Phenotypes for gene: SOCS1 were set to primary immunodeficiency
Review for gene: SOCS1 was set to AMBER
Added comment: PMID 12588885: In coxsackievirus-infected mice cardiac myocyte-specific transgenic expression of SOCS1 inhibited virus-induced signaling of JAK and STAT resulting in increased viral replication, cardiomyopathy, and mortality compared to controls. Inhibition of SOCS in cardiac myocytes increased myocyte resistance to the acute cardiac injury of enteroviral infection. It was suggested that inhibition of SOCS could augment the host-cell antiviral system and might prevent viral-mediated end-organ damage during the early stages of infection.
Sources: Literature
COVID-19 research v0.242 PTPN2 Sarah Leigh gene: PTPN2 was added
gene: PTPN2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PTPN2 was set to Unknown
Publications for gene: PTPN2 were set to 19825843; https://doi.org/10.1101/499988
Phenotypes for gene: PTPN2 were set to primary immunodeficiency
Review for gene: PTPN2 was set to RED
Added comment: https://doi.org/10.1101/499988 reports: genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci).
Sources: Literature
Early onset or syndromic epilepsy v2.56 STARD7 Rebecca Foulger Phenotypes for gene: STARD7 were changed from Epilepsy, familial adult myoclonic, 2, 607876 to Epilepsy, familial adult myoclonic, 2, 607876; Familial adult myoclonic epilepsy-2; FAME-2
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Classified gene: STARD7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Added comment: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Gene: stard7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.54 STARD7 Rebecca Foulger gene: STARD7 was added
gene: STARD7 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Added comment: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.

OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' (previously associated with ADRA2B) is now associated with the STARD7 gene.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger commented on gene: ADRA2B: Added 'for-review' tag to alert GLH to downgraded rating.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Classified gene: ADRA2B as Red List (low evidence)
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Added comment: Comment on list classification: Downgraded rating from Amber to Red following PMID:31664034 (2019) publication that finds an alternative cause for epilepsy in the earlier reported patients, suggesting the the ADRA2B allele is not causative. MIM:607876 is now associated with a repeat expansion in STARD7, and not ADRA2B.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Gene: adra2b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.52 ADRA2B Rebecca Foulger Publications for gene: ADRA2B were set to 11701600
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:18231815: Direct sequencing of the ADRA2B gene in pedigrees from southern Italy that were described as having familial adult myoclonic epilepsy by Madia et al. (2008) did not reveal any pathogenic mutations.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Added comment: Comment on phenotypes: OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' is now associated with the STARD7 gene. Therefore removed MIM:607876 from the phenotype field of ADRA2B.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Phenotypes for gene: ADRA2B were changed from Epilepsy, myoclonic, familial adult, 2, 607876 to Cortical myoclonus and epilepsy
Cholestasis v1.8 TMEM67 Ivone Leong Tag for-review tag was added to gene: TMEM67.
Cholestasis v1.8 CC2D2A Ivone Leong Phenotypes for gene: CC2D2A were changed from COACH syndrome 216360; Meckel syndrome 6 612284; Joubert syndrome 9 612285 to COACH syndrome 216360; Meckel syndrome 6 612284; Joubert syndrome 9 612285; Congenital hepatic fibrosis; Ciliopathy
Cholestasis v1.7 CC2D2A Ivone Leong Publications for gene: CC2D2A were set to 27959436; 19574260; 18950740
Cholestasis v1.6 CC2D2A Ivone Leong Tag for-review tag was added to gene: CC2D2A.
Cholestasis v1.6 RPGRIP1L Ivone Leong Tag for-review tag was added to gene: RPGRIP1L.
Cholestasis v1.6 RPGRIP1L Ivone Leong Phenotypes for gene: RPGRIP1L were changed from Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360) to Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360); Congenital hepatic fibrosis
Cholestasis v1.5 RPGRIP1L Ivone Leong Publications for gene: RPGRIP1L were set to 17558409; 19574260
Cholestasis v1.4 CC2D2A Miranda Durkie reviewed gene: CC2D2A: Rating: RED; Mode of pathogenicity: ; Publications: 28680603; Phenotypes: ; Mode of inheritance:
Cholestasis v1.4 RPGRIP1L Miranda Durkie reviewed gene: RPGRIP1L: Rating: RED; Mode of pathogenicity: ; Publications: 28680603; Phenotypes: ; Mode of inheritance:
Cholestasis v1.4 TMEM67 Miranda Durkie reviewed gene: TMEM67: Rating: RED; Mode of pathogenicity: ; Publications: 28680603; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.171 CD247 Ivone Leong Classified gene: CD247 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.171 CD247 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green after discussion with the Genomics England Clinical Team. An additional case was found (PMID: 26542031). Therefore, there is enough evidence to promote this gene to Green status.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.171 CD247 Ivone Leong Gene: cd247 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Tag watchlist was removed from gene: SEC61A1.
Tag for-review tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Classified gene: SEC61A1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber after discussion with the Genomics England Clinical Team. As there are only 2 families described it was decided that this gene should be rated as Amber. Also added for-review tag.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 SEC61A1 Ivone Leong Tag watchlist tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 TNFRSF13B Ivone Leong reviewed gene: TNFRSF13B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Classified gene: OAS1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Added comment: Comment on list classification: Upgraded rating from Amber to Green following advice from Helen Brittain (Genomics England Clinical Team): There appear to be three unrelated families with variants and hypogammaglobulinaemia. I think this is a relevant phenotype for immune dysfunction.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Gene: oas1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 MYO5B Rebecca Foulger changed review comment from: Added 'for-review' tag to highlight Red review from Zornitza (lack of published information) vs multiple Green GLH reviews.; to: In agreement with Helen Brittain (Genomics England Clinical Team), added 'for-review' tag to highlight Red review from Zornitza (lack of published information) vs multiple Green GLH reviews.
Rare multisystem ciliopathy disorders v1.125 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
Rare multisystem ciliopathy disorders v1.125 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review of EXOC3L2 on the CAKUT gene panel, and on advice from Helen Brittain (Genomics England Clinical Team).
Rare multisystem ciliopathy disorders v1.125 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.112 DHCR7 Rebecca Foulger Classified gene: DHCR7 as Green List (high evidence)
CAKUT v1.112 DHCR7 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green on advice from Helen Brittain (Genomics England Clinical Team). Helen notes that it meets the inclusion criteria (renal malformations as part of a wider syndromic phenotype). There are other post-natally relevant renal malformations (unilateral agenesis, hydronephrosis and cysts). It is also a gene that we have a biochemical test for, so VUSs would be easier to re-categorise than some genes.
CAKUT v1.112 DHCR7 Rebecca Foulger Gene: dhcr7 has been classified as Green List (High Evidence).
CAKUT v1.111 EXOC3L2 Rebecca Foulger Tag watchlist tag was added to gene: EXOC3L2.
CAKUT v1.111 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
CAKUT v1.111 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Agreed by Helen Brittain (Genomics England clinical team) that Amber rating is appropriate here: only one case that didn't lead to fetal demise. Added 'watchlist' tag awaiting further cases.
CAKUT v1.111 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Marked gene: PTRHD1 as ready
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Added comment: Comment when marking as ready: Considered to have sufficient cases with a relevant phenotype for a green rating.
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.67 PTRHD1 Helen Brittain gene: PTRHD1 was added
gene: PTRHD1 was added to Parkinson Disease and Complex Parkinsonism. Sources: Other
Mode of inheritance for gene: PTRHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRHD1 were set to 30398675; 27134041; 29143421; 27753167
Phenotypes for gene: PTRHD1 were set to Intellectual disability; Parkinsonism
Penetrance for gene: PTRHD1 were set to Complete
Review for gene: PTRHD1 was set to GREEN
Added comment: Please see review in ID panel by Konstantinos Varvagiannis: https://panelapp.genomicsengland.co.uk/panels/285/gene/PTRHD1/

In addition: Personal correspondence about a new diagnosis from within the 100,000 genomes project data. A child presenting with learning difficulties, autism, shuffling gait, calf wasting and normal CK has been detected as having homozygous LOF variants in PTRHD1. Reported as class V via NHS diagnostic lab. In view of this additional case and phenotypic overlap (Intellectual disability and Parkinsonian features), I am adding this gene to the panel as green.
Sources: Other
Intellectual disability v3.65 PTRHD1 Helen Brittain Marked gene: PTRHD1 as ready
Intellectual disability v3.65 PTRHD1 Helen Brittain Added comment: Comment when marking as ready: Further case from personal correspondence. Considered sufficient for a green rating.
Intellectual disability v3.65 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.65 PTRHD1 Helen Brittain Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism, Intellectual disability; Parkinsonism to Intellectual disability; Parkinsonism
Intellectual disability v3.64 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.64 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.63 PTRHD1 Helen Brittain Tag watchlist was removed from gene: PTRHD1.
Intellectual disability v3.63 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.63 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.63 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.63 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.62 PTRHD1 Helen Brittain reviewed gene: PTRHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.5 AMELX Eleanor Williams Phenotypes for gene: AMELX were changed from Amelogenesis imperfecta, type 1E, 301200; Amelogenesis Imperfecta, Type IE, 301200; X-linked hypoplastic amelogenesis imperfecta; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI to Amelogenesis imperfecta, type 1E, 301200; iX-linked hypoplastic amelogenesis imperfecta; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI
Paediatric disorders - additional genes v1.51 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.51 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Additional phenotypes were reported in the fetuses and sibling (who died perinatally) from PMID:24439109 (clubbed feet, facial dysmorphism, pulmonary hypoplasia, bilateral cryptorchidism) although renal agenesis is the primary phenotype and only 2 families from one paper.
Paediatric disorders - additional genes v1.51 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Deleted their comment
Paediatric disorders - additional genes v1.50 TBX18 Rebecca Foulger Classified gene: TBX18 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.50 TBX18 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Three unrelated CAKUT cases in PMID:26235987 (2015) but as Helen Brittain notes, isolated CAKUT phenotype is less relevant for the Paediatric disorders panel.
Paediatric disorders - additional genes v1.50 TBX18 Rebecca Foulger Gene: tbx18 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.49 TBX18 Rebecca Foulger Publications for gene: TBX18 were set to
Paediatric disorders - additional genes v1.49 TBX18 Rebecca Foulger Phenotypes for gene: TBX18 were changed from CAKUT to CAKUT; Congenital anomalies of kidney and urinary tract 2, 143400
CAKUT v1.110 TBX18 Rebecca Foulger Phenotypes for gene: TBX18 were changed from to CAKUT; Renal cysts and diabetes; glomerulocystic kidney disease; hypomagneseamia; Congenital anomalies of kidney and urinary tract 2, 143400
CAKUT v1.109 TBX18 Rebecca Foulger Publications for gene: TBX18 were set to
Paediatric disorders - additional genes v1.48 LRIG2 Rebecca Foulger Classified gene: LRIG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.48 LRIG2 Rebecca Foulger Gene: lrig2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.47 LRIG2 Rebecca Foulger Classified gene: LRIG2 as Green List (high evidence)
Paediatric disorders - additional genes v1.47 LRIG2 Rebecca Foulger Added comment: Comment on list classification: Three unrelated cases reported in PMID:23313374 (Stuart et al., 2013), although in one of the families siblings with the same homozygous variant report differing phenotypes. There is also an animal model. The facial phenotype that occurs alongside the urinary tract phenotype is an abnormal facial expression upon smiling rather than a congenital structural phenotype. Therefore have kept Amber for now awaiting clinical review.
Paediatric disorders - additional genes v1.47 LRIG2 Rebecca Foulger Gene: lrig2 has been classified as Green List (High Evidence).
CAKUT v1.108 LRIG2 Rebecca Foulger Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, Gülpınar O, Süer E, Yalçınkaya F, Gücük A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
Paediatric disorders - additional genes v1.46 LRIG2 Rebecca Foulger commented on gene: LRIG2: PMID:23313374. Stuart et al., 2013 performed exome sequencing in affected siblings from a consanguineous Turkish family with urofacial syndrome. A 1bp deletion variant resulting in premature termination (Glu140AspfsTer6) was found in an 8 year old girl, but also in her 5 year old brother who exhibited the facial features but not CAKUT phenotype. The variant was found in heterozygosity in the unaffected first-cousin parents.

In a second Turkish family with urofacial syndrome, two affected sisters were homozygous for a nonsense LRIG2 variant (R709X). A third case comes from a 5year old Spanish girl compound het for a 1bp deletion (Ser697HisfsTer11) and 371bp insertion variant in LRIG2. Her unaffected parents were each heterozygous for one of the variants.

Facial phenotypes of Urofacial syndrome include grimacing on smiling.
Paediatric disorders - additional genes v1.46 LRIG2 Rebecca Foulger Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, G lp nar O, S er E, Yal nkaya F, G c k A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
Paediatric disorders - additional genes v1.45 LRIG2 Rebecca Foulger Phenotypes for gene: LRIG2 were changed from CAKUT; Congenital bladder disease: dyssynergic, high pressure bladder.; Urofacial syndrome to CAKUT; Urofacial syndrome 2, 615112; Congenital bladder disease: dyssynergic, high pressure bladder.; Urofacial syndrome
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Additional phenotypes were reported in the fetuses and sibling (who died perinatally) from PMID:24439109 (clubbed feet, facial dysmorphism, pulmonary hypoplasia, bilateral cryptorchidism) although renal agenesis is the primary phenotype and only 2 families from one paper.
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.72 ITGA8 Rebecca Foulger changed review comment from: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the variant. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.; to: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the variant. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period and presented with BRA and bilateral cryptorchidism.
Fetal anomalies v1.72 ITGA8 Rebecca Foulger Phenotypes for gene: ITGA8 were changed from RENAL HYPODYSPLASIA/APLASIA 1; Renal hypodysplasia/aplasia 1, 191830 to bilateral renal agenesis; anhydramnios; RENAL HYPODYSPLASIA/APLASIA 1; Renal hypodysplasia/aplasia 1, 191830
Fetal anomalies v1.71 ITGA8 Rebecca Foulger changed review comment from: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the varinat. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.; to: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the variant. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.
COVID-19 research v0.241 CASP3 Catherine Snow Classified gene: CASP3 as Green List (high evidence)
COVID-19 research v0.241 CASP3 Catherine Snow Gene: casp3 has been classified as Green List (High Evidence).
COVID-19 research v0.240 CASP3 Catherine Snow gene: CASP3 was added
gene: CASP3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: CASP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CASP3 were set to 32200494; 24903211; 21160486; 23894522
Phenotypes for gene: CASP3 were set to Kawasaki disease
Added comment: Number of SNPs identified in CASP3 associated with risk of Kawaski Disease. Summarised in PMID:32200494
Sources: Literature
COVID-19 research v0.239 BLK Catherine Snow changed review comment from: Number of SNPs identified in BLK associated with risk of Kawaski Disease
Sources: Literature; to: Number of SNPs identified in BLK associated with risk of Kawaski Disease. Summarised in PMID:32200494
Sources: Literature
COVID-19 research v0.239 BLK Catherine Snow Publications for gene: BLK were set to 22446961; 26182267; 24023612; 25645453
COVID-19 research v0.238 BLK Catherine Snow Classified gene: BLK as Green List (high evidence)
COVID-19 research v0.238 BLK Catherine Snow Gene: blk has been classified as Green List (High Evidence).
COVID-19 research v0.237 BLK Catherine Snow gene: BLK was added
gene: BLK was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: BLK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BLK were set to 22446961; 26182267; 24023612; 25645453
Phenotypes for gene: BLK were set to Kawasaki disease
Review for gene: BLK was set to GREEN
Added comment: Number of SNPs identified in BLK associated with risk of Kawaski Disease
Sources: Literature
Fetal anomalies v1.71 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Fetal anomalies v1.71 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Relevant phenotype (renal agenesis) but currently insufficient evidence (2 unrelated cases from PMID:24439109, and 'probable' rating in Gene2Phenotype) for diagnostic-grade rating.
Fetal anomalies v1.71 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.70 ITGA8 Rebecca Foulger Phenotypes for gene: ITGA8 were changed from RENAL HYPODYSPLASIA/APLASIA 1 to RENAL HYPODYSPLASIA/APLASIA 1; Renal hypodysplasia/aplasia 1, 191830
Fetal anomalies v1.70 ITGA8 Rebecca Foulger Publications for gene: ITGA8 were set to
Fetal anomalies v1.69 ITGA8 Rebecca Foulger commented on gene: ITGA8: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the varinat. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.
Paediatric disorders - additional genes v1.44 GATA3 Rebecca Foulger Classified gene: GATA3 as Green List (high evidence)
Paediatric disorders - additional genes v1.44 GATA3 Rebecca Foulger Gene: gata3 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.43 GATA3 Rebecca Foulger Classified gene: GATA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.43 GATA3 Rebecca Foulger Added comment: Comment on list classification: Updated from Amber to Green awaiting GLH review. GATA3 HDR syndrome includes hypoparathyroidism and sensorineural deafness in addition to renal dysplasia.
Paediatric disorders - additional genes v1.43 GATA3 Rebecca Foulger Gene: gata3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.42 GATA3 Rebecca Foulger commented on gene: GATA3: PMID:11389161. Muroya et al., 2001 report 9 Japanese families with HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia). Heterozygous gross deletions were reported by FISH in 4 families. Sequence analysis showed heterozygous novel variants in 3 families. 2 families had no GATA3 abnormalities detected.
Paediatric disorders - additional genes v1.42 GATA3 Rebecca Foulger commented on gene: GATA3: GATA3 has an Amber rating on Clefting panel v2.3.
Paediatric disorders - additional genes v1.42 REN Rebecca Foulger Classified gene: REN as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.42 REN Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review as to whether renal phenotypes are sufficient for inclusion on the Paediatric disorders panel.
Paediatric disorders - additional genes v1.42 REN Rebecca Foulger Gene: ren has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.41 REN Rebecca Foulger commented on gene: REN: PMID:31736371. He et al., performed a study to identify the potentially pathogenic gene variants that contribute to the AR renal tubular dysgenesis (RTD) in the aborted fetus. WES was performed on an aborted fetus and his parents. Compound heterozygous variants (c.963T>A, p.Y321X and c.492+1G>A splicing site mutation) were identified in the fetus, one inherited from each parent.
Paediatric disorders - additional genes v1.41 REN Rebecca Foulger Publications for gene: REN were set to
Fetal anomalies v1.69 REN Rebecca Foulger Publications for gene: REN were set to
Fetal anomalies v1.68 REN Rebecca Foulger commented on gene: REN: PMID:31736371. He et al., performed a study to identify the potentially pathogenic gene variants that contribute to the AR renal tubular dysgenesis (RTD) in an aborted fetus. WES was performed on the fetus and his parents. Compound heterozygous variants (c.963T>A, p.Y321X and c.492+1G>A splicing site mutation) were identified in the fetus, one inherited from each parent.
Paediatric disorders - additional genes v1.40 REN Rebecca Foulger Added comment: Comment on mode of inheritance: Hyperuricemic nephropathy, familial juvenile 2, 613092 has AD inheritance, and Renal tubular dysgenesis, 267430 has AR inheritance.
Paediatric disorders - additional genes v1.40 REN Rebecca Foulger Mode of inheritance for gene: REN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric disorders - additional genes v1.39 REN Rebecca Foulger Phenotypes for gene: REN were changed from CAKUT; [Hyperproreninemia]; Renal Tubular Dysgenesis to CAKUT; [Hyperproreninemia]; Hyperuricemic nephropathy, familial juvenile 2, 613092; Renal tubular dysgenesis, 267430
Paediatric disorders - additional genes v1.38 GREB1L Rebecca Foulger Classified gene: GREB1L as Green List (high evidence)
Paediatric disorders - additional genes v1.38 GREB1L Rebecca Foulger Gene: greb1l has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.37 GREB1L Rebecca Foulger Classified gene: GREB1L as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.37 GREB1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green awaiting GLH review: although the predominant phenotype is renal defects, inner ear malformations are also included in the phenotypic spectrum (PMID:29955957).
Paediatric disorders - additional genes v1.37 GREB1L Rebecca Foulger Gene: greb1l has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.36 GREB1L Rebecca Foulger Phenotypes for gene: GREB1L were changed from CAKUT; Renal hypodysplasia/aplasia 3, 617805 to CAKUT; Renal hypodysplasia/aplasia 3, 617805; inner ear malformations
Paediatric disorders - additional genes v1.36 GREB1L Rebecca Foulger Publications for gene: GREB1L were set to 29100091; 29220675; 29261186
Paediatric disorders - additional genes v1.35 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29955957. Schrauwen et al., 2018 performed trio-based WES sequencing in young unrelated subjects with inner ear malformations, and identified novel de novo LOF variants in GREB1L (Glu1410fs and Arg328*) in 2 affected subjects with absent cochleae and eighth cranial nerve malformations.
Paediatric disorders - additional genes v1.35 GREB1L Rebecca Foulger changed review comment from: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L.
Fetal cases with bilateral kidney agenesis include p.Gln528Argfs*12 (also present in their alive brother with unilateral kidney agenesis) and splice variant c.4369−1G>C.; to: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L. Family histories and phenotypes suggest incomplete penetrance.
Paediatric disorders - additional genes v1.35 GREB1L Rebecca Foulger Publications for gene: GREB1L were set to 29100091; 29220675
Paediatric disorders - additional genes v1.34 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L.
Fetal cases with bilateral kidney agenesis include p.Gln528Argfs*12 (also present in their alive brother with unilateral kidney agenesis) and splice variant c.4369−1G>C.
Paediatric disorders - additional genes v1.34 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29261186 (Boissel et al., 2018) performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies. In 2 cases who presented with renal agenesis, de novo variants in GREB1L were identified (p.A968V and p.S98X).
Paediatric disorders - additional genes v1.34 CHRNA3 Rebecca Foulger Phenotypes for gene: CHRNA3 were changed from CAKUT; dysautonomia; functional lower urinary tract obstruction and secondary CAKUT to CAKUT; dysautonomia; Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, 191800
Paediatric disorders - additional genes v1.33 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as Green List (high evidence)
Paediatric disorders - additional genes v1.33 CHRNA3 Rebecca Foulger Added comment: Comment on list classification: Updated gene from Amber to Green, awaiting GLH review. CAKUT is secondary to bladder obstruction, and therefore additional congenital defects may present (PMID:31708116).
Paediatric disorders - additional genes v1.33 CHRNA3 Rebecca Foulger Gene: chrna3 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.32 CHRNA3 Rebecca Foulger changed review comment from: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA2 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.; to: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA3 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.
Paediatric disorders - additional genes v1.32 AGTR1 Rebecca Foulger Classified gene: AGTR1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.32 AGTR1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now. Plenty of literature suggesting links between AGTR1 polymorphisms and disease risk for e.g. pulmonary arterial hypertension (e.g. PMID:25603901) but key congenital disorder seems to be renal dysgenesis (PMID:16116425).
Paediatric disorders - additional genes v1.32 AGTR1 Rebecca Foulger Gene: agtr1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.31 AGTR1 Rebecca Foulger commented on gene: AGTR1: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1.
Paediatric disorders - additional genes v1.31 ANOS1 Rebecca Foulger Classified gene: ANOS1 as Green List (high evidence)
Paediatric disorders - additional genes v1.31 ANOS1 Rebecca Foulger Gene: anos1 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.30 ANOS1 Rebecca Foulger Classified gene: ANOS1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.30 ANOS1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green, awaiting GLH review. Sufficient cases to support Kallman syndrome association, which can present with phenotypes beyond renal, some of which could be detected at birth.
Paediatric disorders - additional genes v1.30 ANOS1 Rebecca Foulger Gene: anos1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.29 ANOS1 Rebecca Foulger commented on gene: ANOS1: PMID:16423815. Trarbach et al 2005 report 12 Kallmann syndrome (KS) patients. Two ANOS1 variants (referred to as KAL-1 gene) were found in 2 KS patients (Arg191X, and del1956C leading to a premature stop codon at 617). A patient with a KAL-1 microdeletion was also reported. Renal agenesis and bimanual synkinesis were observed in these cases.
Paediatric disorders - additional genes v1.29 ANOS1 Rebecca Foulger Publications for gene: ANOS1 were set to 1518845
Paediatric disorders - additional genes v1.28 ANOS1 Rebecca Foulger Phenotypes for gene: ANOS1 were changed from CAKUT; Kallman syndrome; Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) to CAKUT; Kallman syndrome; Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), 308700
Paediatric disorders - additional genes v1.27 AGT Rebecca Foulger Classified gene: AGT as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.27 AGT Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now: renal tubulogenesis is key phenotype and therefore CAKUT may be isolated.
Paediatric disorders - additional genes v1.27 AGT Rebecca Foulger Gene: agt has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.68 ACTG2 Rebecca Foulger Publications for gene: ACTG2 were set to 25998219; 30712878
Paediatric disorders - additional genes v1.26 ACTG2 Rebecca Foulger Classified gene: ACTG2 as Green List (high evidence)
Paediatric disorders - additional genes v1.26 ACTG2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on papers demonstrating a role in MMIHS (e.g. PMID:27481187, 25998219), thereby broadening phenotype from isolated CAKUT.
Paediatric disorders - additional genes v1.26 ACTG2 Rebecca Foulger Gene: actg2 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.25 ACTG2 Rebecca Foulger changed review comment from: PMID:27481187 Moreno et al., 201. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).; to: PMID:27481187 Moreno et al., 2016. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).
Paediatric disorders - additional genes v1.25 ACTG2 Rebecca Foulger commented on gene: ACTG2: PMID:27481187 Moreno et al., 201. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).
Paediatric disorders - additional genes v1.25 ACTG2 Rebecca Foulger Publications for gene: ACTG2 were set to 25998219
Paediatric disorders - additional genes v1.24 ACTG2 Rebecca Foulger changed review comment from: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMHIS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMHIS (MIM:249210) is associated with MYLK.; to: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMIHS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMIHS (MIM:249210) is associated with MYLK.
Paediatric disorders - additional genes v1.24 ACE Rebecca Foulger Classified gene: ACE as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.24 ACE Rebecca Foulger Added comment: Comment on list classification: Key papers report renal tubular dysgenesis. In absence of additional morphological features, keep Amber awaiting GLH review.
Paediatric disorders - additional genes v1.24 ACE Rebecca Foulger Gene: ace has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.23 ACE Rebecca Foulger commented on gene: ACE: PMID:30058238 (Bhowmik et al., 2018) report a 32-week old fetus with severe early onset oligohydramnios. A similarly affected sibling was reported from a previous pregnancy. Exome sequencing revealed a homozygous 3' splice-site variant in intron 17 of ACE gene, which confirmed AR renal tubular dysgenesis. It also facilitated prenatal diagnosis in a subsequent pregnancy.
Paediatric disorders - additional genes v1.23 ACE Rebecca Foulger commented on gene: ACE: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1.
CAKUT v1.107 ACE Rebecca Foulger Publications for gene: ACE were set to
COVID-19 research v0.235 Eleanor Williams Panel name changed from Viral susceptibility to COVID-19 research
List of related panels changed from to Viral susceptibility
COVID-19 research v0.234 ANPEP Eleanor Williams gene: ANPEP was added
gene: ANPEP was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: ANPEP was set to Unknown
Publications for gene: ANPEP were set to 28643204
Added comment: PMID: 28643204 - de Wilde et al 2018 - in a review of known coronavirus entry receptors APN/ANPEP is listed as a entry receptor for several Alphacoronaviruses (Table 1). Sars-cov-2 is a Betacoronavirus.
Sources: Literature
COVID-19 research v0.233 DPP4 Eleanor Williams Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093; https://doi.org/10.1101/2020.04.30.071274
COVID-19 research v0.232 DPP4 Eleanor Williams commented on gene: DPP4: PMID: 31883094 - Leist et al 2020 - describe the generation of the 288-330+/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330).
COVID-19 research v0.232 DPP4 Eleanor Williams commented on gene: DPP4
COVID-19 research v0.232 ACE2 Eleanor Williams changed review comment from: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations.; to: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations. East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues.
COVID-19 research v0.232 ACE2 Eleanor Williams Publications for gene: ACE2 were set to 14647384; 15897467; 16007097; 32142651; 32015507
COVID-19 research v0.231 ACE2 Eleanor Williams commented on gene: ACE2: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations.
COVID-19 research v0.231 HSPA5 Eleanor Williams gene: HSPA5 was added
gene: HSPA5 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: HSPA5 was set to Unknown
Publications for gene: HSPA5 were set to 3216948
Review for gene: HSPA5 was set to RED
Added comment: PMID:3216948 - Ibrahim et al 2020 - predict that HSPA5 (GRP78) might bind with COVID-19 spike
Sources: Literature
COVID-19 research v0.230 ACE2 Eleanor Williams commented on gene: ACE2: PMID: 32249956 Hussain et al 2020 - show through molecular modelling that ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein of SARS-CoV-2
COVID-19 research v0.230 TMPRSS2 Eleanor Williams Publications for gene: TMPRSS2 were set to 31488196; 32142651; 24227843; 25904605; 24600012; 24522916; 32327758
COVID-19 research v0.229 TMPRSS2 Eleanor Williams Deleted their review
COVID-19 research v0.229 TMPRSS2 Eleanor Williams Deleted their comment
COVID-19 research v0.229 ITPKC Catherine Snow Publications for gene: ITPKC were set to 18084290; 20045869
COVID-19 research v0.228 ITPKC Catherine Snow Classified gene: ITPKC as Green List (high evidence)
COVID-19 research v0.228 ITPKC Catherine Snow Gene: itpkc has been classified as Green List (High Evidence).
COVID-19 research v0.227 FCGR2A Catherine Snow edited their review of gene: FCGR2A: Added comment: Has been identified as a risk loci for Kawasaki disease.; Changed publications: 19494086, 12752683, 16185324, 22446962
COVID-19 research v0.227 ORAI1 Catherine Snow reviewed gene: ORAI1: Rating: ; Mode of pathogenicity: None; Publications: 30853710, 26789410; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.227 TMPRSS2 Eleanor Williams Added comment: Comment on publications: Adding pubmed:32327758 - using single cell RNA-sequencing they confirmed the expression of ACE2 in multiple tissues shown in previous studies with added information on tissues not previously investigated, including nasal epithelium and cornea and its co-expression with TMPRSS2
COVID-19 research v0.227 TMPRSS2 Eleanor Williams Publications for gene: TMPRSS2 were set to 31488196; 32142651; 24227843; 25904605; 24600012; 24522916
COVID-19 research v0.226 SCN5A Eleanor Williams changed review comment from: PMID: 32380288 Giudicessi et al 2020 - discuss the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic.; to: PMID: 32380288 Giudicessi et al 2020 - discuss the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic.

Keeping red for now, as this paper is speculation - no real data.
COVID-19 research v0.226 SCN5A Eleanor Williams Publications for gene: SCN5A were set to
COVID-19 research v0.225 SCN5A Eleanor Williams reviewed gene: SCN5A: Rating: ; Mode of pathogenicity: None; Publications: 32380288; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.225 APOE Eleanor Williams Classified gene: APOE as Amber List (moderate evidence)
COVID-19 research v0.225 APOE Eleanor Williams Added comment: Comment on list classification: Rating amber as one study reported showing that a variant (ApoE e4 allele) is associated with hospitalization with COVID-19.
COVID-19 research v0.225 APOE Eleanor Williams Gene: apoe has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.224 APOE Eleanor Williams gene: APOE was added
gene: APOE was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: APOE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOE were set to https://doi.org/10.1101/2020.05.07.20094409
Phenotypes for gene: APOE were set to dementia
Added comment: Preprint: https://doi.org/10.1101/2020.05.07.20094409 Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes.
ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the
excess incidence of COVID-19 in Blacks.
Sources: Literature
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Tag for-review tag was added to gene: MESD.
Osteogenesis imperfecta v2.6 MESD Eleanor Williams changed review comment from: Gene suggested by Alistair Pagnamenta.

Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM.

PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking.
Sources: Literature; to: Gene suggested by Alistair Pagnamenta.

Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM.

PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking.

Alistair Pagnamenta notes that there is a lack of sibling data.
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Classified gene: MESD as Green List (high evidence)
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. More than three families reported, with plausible disease causing variants.
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Gene: mesd has been classified as Green List (High Evidence).
Osteogenesis imperfecta v2.5 MESD Eleanor Williams Phenotypes for gene: MESD were changed from to Osteogenesis imperfecta, type XX, 618644
Osteogenesis imperfecta v2.4 MESD Eleanor Williams gene: MESD was added
gene: MESD was added to Osteogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MESD were set to 31564437
Added comment: Gene suggested by Alistair Pagnamenta.

Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM.

PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking.
Sources: Literature
Fetal anomalies v1.67 GREB1L Rebecca Foulger commented on gene: GREB1L: Added 'for-review' tag: Gene has been added and assessed by Curation team but not yet reviewed by clinical team.
Fetal anomalies v1.67 GREB1L Rebecca Foulger Tag for-review tag was added to gene: GREB1L.
Fetal anomalies v1.67 GREB1L Rebecca Foulger Classified gene: GREB1L as Green List (high evidence)
Fetal anomalies v1.67 GREB1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following curation of PMID:29100091 which presents additional fetal cases of renal agenesis and GREB1L variants. Sufficient evidence for association of GREB1L with kidney agenesis, and phenotype can present fetally.
Fetal anomalies v1.67 GREB1L Rebecca Foulger Gene: greb1l has been classified as Green List (High Evidence).
Fetal anomalies v1.66 GREB1L Rebecca Foulger Publications for gene: GREB1L were set to 29261186
Fetal anomalies v1.65 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L.
Fetal cases with bilateral kidney agenesis include p.Gln528Argfs*12 (also present in their alive brother with unilateral kidney agenesis) and splice variant c.4369−1G>C.
Fetal anomalies v1.65 GREB1L Rebecca Foulger Classified gene: GREB1L as Amber List (moderate evidence)
Fetal anomalies v1.65 GREB1L Rebecca Foulger Added comment: Comment on list classification: Added to panel and set rating to Amber. Not yet associated with a disorder in Gene2Phenotype, but 2 fetal cases presented in PMID:29261186. Renal agenesis phenotype is relevant to the panel. Therefore Amber awaiting further cases.
Fetal anomalies v1.65 GREB1L Rebecca Foulger Gene: greb1l has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.64 GREB1L Rebecca Foulger gene: GREB1L was added
gene: GREB1L was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GREB1L were set to 29261186
Phenotypes for gene: GREB1L were set to Renal hypodysplasia/aplasia 3, 617805; renal agenesis
Added comment: Added to Fetal panel based on PMID:29261186 (Boissel et al., 2018) who performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies. In 2 cases presenting with renal agenesis, de novo variants in GREB1L were identified (p.A968V and p.S98X).
Sources: Literature
Paediatric disorders - additional genes v1.23 CHRNA3 Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review as to whether phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.23 CHRNA3 Rebecca Foulger Phenotypes for gene: CHRNA3 were changed from CAKUT; dysautonomia to CAKUT; dysautonomia; functional lower urinary tract obstruction and secondary CAKUT
Paediatric disorders - additional genes v1.22 CHRNA3 Rebecca Foulger commented on gene: CHRNA3: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA2 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.
Paediatric disorders - additional genes v1.22 ANOS1 Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review as to whether phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.22 ANOS1 Rebecca Foulger changed review comment from: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.; to: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.
Paediatric disorders - additional genes v1.22 ANOS1 Rebecca Foulger Publications for gene: ANOS1 were set to
Paediatric disorders - additional genes v1.21 ANOS1 Rebecca Foulger commented on gene: ANOS1: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.
Paediatric disorders - additional genes v1.21 AGT Rebecca Foulger commented on gene: AGT: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1.
Paediatric disorders - additional genes v1.21 AGT Rebecca Foulger changed review comment from: Added to Paediatric disorders - additional genes panel, based on Green rating on CAKUT panel V1.106. Note that AGT is on V14.137 Paediatric panel already but with Red rating.; to: Added to Paediatric disorders - additional genes panel, based on Green rating on CAKUT panel V1.106. Note that AGT is on V14.137 Paediatric disorders panel already but with Red rating.
Paediatric disorders - additional genes v1.21 AGT Rebecca Foulger Phenotypes for gene: AGT were changed from CAKUT; {Hypertension, essential, susceptibility to}, 145500{Preeclampsia, susceptibility to}Renal tubular dysgenesis, 267430; Renal Tubular Dysgenesis to Renal tubular dysgenesis, 267430; CAKUT
Paediatric disorders - additional genes v1.20 AGT Rebecca Foulger Publications for gene: AGT were set to
Paediatric disorders - additional genes v1.19 ACTG2 Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review for inclusion on Paediatric disorders panel: whether CAKUT phenotype presents alongside additional congenital malformations.
Fetal anomalies v1.63 ACTG2 Rebecca Foulger Mode of pathogenicity for gene: ACTG2 was changed from to Other
Paediatric disorders - additional genes v1.19 ACTG2 Rebecca Foulger commented on gene: ACTG2: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMHIS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMHIS (MIM:249210) is associated with MYLK.
Fetal anomalies v1.62 ACTG2 Rebecca Foulger Phenotypes for gene: ACTG2 were changed from Visceral myopathy 155310 to Visceral myopathy 155310; Fetal Megacystis
Fetal anomalies v1.61 ACTG2 Rebecca Foulger Publications for gene: ACTG2 were set to
Paediatric disorders - additional genes v1.19 ACTG2 Rebecca Foulger Phenotypes for gene: ACTG2 were changed from CAKUT; Megacystis-microcolon intestinal hypoperistalsis syndrome; visceral myopathy; Berdon syndrome to CAKUT; Megacystis-microcolon intestinal hypoperistalsis syndrome; Visceral myopathy, 155310; Berdon syndrome
Paediatric disorders - additional genes v1.18 ACE Rebecca Foulger Publications for gene: ACE were set to 16116425; 22095942
Paediatric disorders - additional genes v1.17 ACE Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review for inclusion on Paediatric disorders panel: whether CAKUT phenotype presents alongside additional congenital malformations.
Fetal anomalies v1.60 ACE Rebecca Foulger commented on gene: ACE: PMID:30058238 (Bhowmik et al., 2018) report a 32-week old fetus with severe early onset oligohydramnios. A similarly affected sibling was reported from a previous pregnancy. Exome sequencing revealed a homozygous 3' splice-site variant in intron 17 of ACE gene, which confirmed AR renal tubular dysgenesis. It also facilitated prenatal diagnosis in a subsequent pregnancy.
Fetal anomalies v1.60 ACE Rebecca Foulger Publications for gene: ACE were set to
Paediatric disorders - additional genes v1.17 ACE Rebecca Foulger Publications for gene: ACE were set to
Fetal anomalies v1.59 GJB2 Rebecca Foulger commented on gene: GJB2: Note that GJB2 is no longer present on the DD panel of Gene2Phenotype. All GJB2 phenotypes (May 2020) are associated with the Gene2Phenotype skin panel. Red rating is still appropriate for this Fetal panel.
COVID-19 research v0.223 DDX58 Sarah Leigh Classified gene: DDX58 as Amber List (moderate evidence)
COVID-19 research v0.223 DDX58 Sarah Leigh Added comment: Comment on list classification: Wild type DDX58 confers detection and eradication of replicating viral genomes, variants in this gene could therefore interfere with this mechanism.
COVID-19 research v0.223 DDX58 Sarah Leigh Gene: ddx58 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.222 DDX58 Sarah Leigh Publications for gene: DDX58 were set to 21939710; 16625202
COVID-19 research v0.221 DDX58 Sarah Leigh gene: DDX58 was added
gene: DDX58 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: DDX58 was set to Unknown
Publications for gene: DDX58 were set to 21939710; 16625202
Added comment: PMID 21939710 found DDX5 (formerly known as RIGI) was essential for virus-induced expression of IRF3 and concluded that DDX5 is essential for detection and eradication of replicating viral genomes. PMID 16625202 reported that DDX58 is essential for the production of interferons in response to certain RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus.
Sources: Literature
Paediatric disorders - additional genes v1.16 TBX18 Rebecca Foulger Classified gene: TBX18 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.16 TBX18 Rebecca Foulger Gene: tbx18 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.15 REN Rebecca Foulger Classified gene: REN as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.15 REN Rebecca Foulger Gene: ren has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.14 LRIG2 Rebecca Foulger Classified gene: LRIG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.14 LRIG2 Rebecca Foulger Gene: lrig2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.13 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.13 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.12 GREB1L Rebecca Foulger Classified gene: GREB1L as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.12 GREB1L Rebecca Foulger Gene: greb1l has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.11 GATA3 Rebecca Foulger Classified gene: GATA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.11 GATA3 Rebecca Foulger Gene: gata3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.10 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.10 CHRNA3 Rebecca Foulger Gene: chrna3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.9 ANOS1 Rebecca Foulger Classified gene: ANOS1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.9 ANOS1 Rebecca Foulger Gene: anos1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.8 AGTR1 Rebecca Foulger Classified gene: AGTR1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.8 AGTR1 Rebecca Foulger Gene: agtr1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.7 AGT Rebecca Foulger Classified gene: AGT as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.7 AGT Rebecca Foulger Gene: agt has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.6 ACTG2 Rebecca Foulger Classified gene: ACTG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.6 ACTG2 Rebecca Foulger Gene: actg2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.5 ACE Rebecca Foulger Classified gene: ACE as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.5 ACE Rebecca Foulger Gene: ace has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.220 DPP4 Sarah Leigh Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093
COVID-19 research v0.219 DPP4 Sarah Leigh Classified gene: DPP4 as Amber List (moderate evidence)
COVID-19 research v0.219 DPP4 Sarah Leigh Gene: dpp4 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.218 DPP4 Sarah Leigh gene: DPP4 was added
gene: DPP4 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: DPP4 was set to Unknown
Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093
Review for gene: DPP4 was set to AMBER
Added comment: DPP4 is a functional receptor for human coronavirus-Erasmus Medical Center (hCoV-EMC), also known as Middle East respiratory syndrome coronavirus (MERS-CoV). Blades 4 and 5 of the 8-blade beta-propeller region of DPP4 confer binding and susceptibility to MERS-CoV (PMID 24554656). Rhodants are not susceptible to MERS-CoV, however, a mouse models expressing human DPP4 became infected with MERS-CoV (PMID 24599590; 25589660; 26124093).
Sources: Literature
Paediatric disorders - additional genes v1.4 TBX18 Rebecca Foulger Tag for-review tag was added to gene: TBX18.
Paediatric disorders - additional genes v1.4 TBX18 Rebecca Foulger commented on gene: TBX18: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 GREB1L Rebecca Foulger Tag for-review tag was added to gene: GREB1L.
Paediatric disorders - additional genes v1.4 GREB1L Rebecca Foulger commented on gene: GREB1L: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 REN Rebecca Foulger Tag for-review tag was added to gene: REN.
Paediatric disorders - additional genes v1.4 REN Rebecca Foulger commented on gene: REN: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 LRIG2 Rebecca Foulger Tag for-review tag was added to gene: LRIG2.
Paediatric disorders - additional genes v1.4 LRIG2 Rebecca Foulger commented on gene: LRIG2: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ITGA8 Rebecca Foulger Tag for-review tag was added to gene: ITGA8.
Paediatric disorders - additional genes v1.4 ITGA8 Rebecca Foulger commented on gene: ITGA8: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 GATA3 Rebecca Foulger Tag for-review tag was added to gene: GATA3.
Paediatric disorders - additional genes v1.4 GATA3 Rebecca Foulger commented on gene: GATA3: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 CHRNA3 Rebecca Foulger Tag for-review tag was added to gene: CHRNA3.
Paediatric disorders - additional genes v1.4 CHRNA3 Rebecca Foulger commented on gene: CHRNA3: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ANOS1 Rebecca Foulger Tag for-review tag was added to gene: ANOS1.
Paediatric disorders - additional genes v1.4 ANOS1 Rebecca Foulger commented on gene: ANOS1: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 AGTR1 Rebecca Foulger Tag for-review tag was added to gene: AGTR1.
Paediatric disorders - additional genes v1.4 AGTR1 Rebecca Foulger commented on gene: AGTR1: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 AGT Rebecca Foulger Tag for-review tag was added to gene: AGT.
Paediatric disorders - additional genes v1.4 AGT Rebecca Foulger commented on gene: AGT: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ACTG2 Rebecca Foulger commented on gene: ACTG2: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ACTG2 Rebecca Foulger Tag for-review tag was added to gene: ACTG2.
Paediatric disorders - additional genes v1.4 ACE Rebecca Foulger commented on gene: ACE: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ACE Rebecca Foulger Tag for-review tag was added to gene: ACE.
Paediatric disorders - additional genes v1.4 AGT Rebecca Foulger commented on gene: AGT
Paediatric disorders - additional genes v1.4 TBX18 Rebecca Foulger commented on gene: TBX18
Paediatric disorders - additional genes v1.4 LRIG2 Rebecca Foulger commented on gene: LRIG2
Paediatric disorders - additional genes v1.4 ITGA8 Rebecca Foulger commented on gene: ITGA8
Paediatric disorders - additional genes v1.4 GATA3 Rebecca Foulger commented on gene: GATA3
Paediatric disorders - additional genes v1.4 REN Rebecca Foulger commented on gene: REN
Paediatric disorders - additional genes v1.4 GREB1L Rebecca Foulger commented on gene: GREB1L
Paediatric disorders - additional genes v1.4 CHRNA3 Rebecca Foulger commented on gene: CHRNA3
Paediatric disorders - additional genes v1.4 ANOS1 Rebecca Foulger commented on gene: ANOS1
Paediatric disorders - additional genes v1.4 AGTR1 Rebecca Foulger commented on gene: AGTR1
Paediatric disorders - additional genes v1.4 ACTG2 Rebecca Foulger commented on gene: ACTG2
Paediatric disorders - additional genes v1.4 ACE Rebecca Foulger commented on gene: ACE
Paediatric disorders - additional genes v1.3 AGT Rebecca Foulger gene: AGT was added
gene: AGT was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AGT were set to CAKUT; {Hypertension, essential, susceptibility to}, 145500{Preeclampsia, susceptibility to}Renal tubular dysgenesis, 267430; Renal Tubular Dysgenesis
Paediatric disorders - additional genes v1.3 TBX18 Rebecca Foulger gene: TBX18 was added
gene: TBX18 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: TBX18 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TBX18 were set to CAKUT
Paediatric disorders - additional genes v1.3 LRIG2 Rebecca Foulger gene: LRIG2 was added
gene: LRIG2 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: LRIG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, G lp nar O, S er E, Yal nkaya F, G c k A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
Phenotypes for gene: LRIG2 were set to CAKUT; Congenital bladder disease: dyssynergic, high pressure bladder.; Urofacial syndrome
Paediatric disorders - additional genes v1.3 ITGA8 Rebecca Foulger gene: ITGA8 was added
gene: ITGA8 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ITGA8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITGA8 were set to CAKUT; Renal hypodysplasia/aplasia 1, 191830
Paediatric disorders - additional genes v1.3 GATA3 Rebecca Foulger gene: GATA3 was added
gene: GATA3 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: GATA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GATA3 were set to CAKUT; Hypoparathyroidism, sensorineural deafness, and renal dysplasia, 146255; Hypoparathyroidism, Sensorineural Deafness, and Renal Disease
Paediatric disorders - additional genes v1.3 REN Rebecca Foulger gene: REN was added
gene: REN was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: REN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: REN were set to CAKUT; [Hyperproreninemia]; Renal Tubular Dysgenesis
Paediatric disorders - additional genes v1.3 GREB1L Rebecca Foulger gene: GREB1L was added
gene: GREB1L was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to 29100091; 29220675
Phenotypes for gene: GREB1L were set to CAKUT; Renal hypodysplasia/aplasia 3, 617805
Paediatric disorders - additional genes v1.3 CHRNA3 Rebecca Foulger gene: CHRNA3 was added
gene: CHRNA3 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: CHRNA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA3 were set to 31708116
Phenotypes for gene: CHRNA3 were set to CAKUT; dysautonomia
Paediatric disorders - additional genes v1.3 ANOS1 Rebecca Foulger gene: ANOS1 was added
gene: ANOS1 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ANOS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: ANOS1 were set to CAKUT; Kallman syndrome; Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1)
Paediatric disorders - additional genes v1.3 AGTR1 Rebecca Foulger gene: AGTR1 was added
gene: AGTR1 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AGTR1 were set to CAKUT; Hypertension, essential, 145500; Renal Tubular Dysgenesis; Renal tubular dysgenesis, 267430
Paediatric disorders - additional genes v1.3 ACTG2 Rebecca Foulger gene: ACTG2 was added
gene: ACTG2 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ACTG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTG2 were set to 25998219
Phenotypes for gene: ACTG2 were set to CAKUT; Megacystis-microcolon intestinal hypoperistalsis syndrome; visceral myopathy; Berdon syndrome
Paediatric disorders - additional genes v1.3 ACE Rebecca Foulger gene: ACE was added
gene: ACE was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ACE were set to CAKUT; Renal Tubular Dysgenesis
COVID-19 research v0.217 MX1 Sarah Leigh gene: MX1 was added
gene: MX1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: MX1 was set to Unknown
Publications for gene: MX1 were set to 3162334; 14872030; 21935451; https://doi.org/10.1101/2020.05.04.075911
Review for gene: MX1 was set to AMBER
Added comment: MX1 is an interferon-induced protein with antiviral activity (PMID 3162334).
PMID 14872030 c.-88G>T was more frequent in 40 unrelated Japanese patients with subacute sclerosing panencephalitisis (associated with CNS infection with measles virus), than in 90 controls (0.42 in patients vs 0.29 in controls). Variant c.-88G>T results increased MX1 expression, the authors suggest that MX1 may paradoxically enable persistence of the virus in the CNS by attenuating viral gene expression and preventing complete immunologic clearance.
PMID 21935451 concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic West Nile viru infection and disease progression.
Preprint https://doi.org/10.1101/2020.05.04.075911 Reports that rs35074065 of TMPRSS2 results in increased expression of the nearby gene MX1.
Sources: Literature
COVID-19 research v0.216 BST2 Rebecca Foulger Classified gene: BST2 as Red List (low evidence)
COVID-19 research v0.216 BST2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as a Red gene: present in latest release of UniProt COVID portal. Plays a role in tethering viruses to the host cell to block viral release. Recent research (PMID:31199522) shows interaction with SARS-CoV spike protein, which inhibits BST2 function and allows viral release.
COVID-19 research v0.216 BST2 Rebecca Foulger Gene: bst2 has been classified as Red List (Low Evidence).
COVID-19 research v0.215 BST2 Rebecca Foulger commented on gene: BST2: PMID:31199522. Wang et al., 2019 show that SARS-CoV spike (S) glycoprotein antagonises the BST2 tethering of SARS-CoV via BST2 downregulation. The authors show colocalization BST2 and SARS-CoV S protein.
COVID-19 research v0.215 BST2 Rebecca Foulger gene: BST2 was added
gene: BST2 was added to Viral susceptibility. Sources: Literature,Other
Mode of inheritance for gene: BST2 was set to Unknown
Publications for gene: BST2 were set to 31199522
Added comment: BST2 is present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/Q10589. BST2 is an IFN-induced antiviral host restriction factor which physically blocks the release of viruses by directly tethering nascent virions to the membranes of infected cells.
Sources: Literature, Other
COVID-19 research v0.214 TMPRSS2 Sarah Leigh changed review comment from: Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.; to: Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele of rs35074065, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G variant viral Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.
COVID-19 research v0.214 KPNA2 Rebecca Foulger Classified gene: KPNA2 as Red List (low evidence)
COVID-19 research v0.214 KPNA2 Rebecca Foulger Added comment: Comment on list classification: Added KPNA2 to the panel as a Red gene. Present in the latest UniProt COVID portal release based on functional data that show an interaction with SARS-COVID viral ORF6 protein.
COVID-19 research v0.214 KPNA2 Rebecca Foulger Gene: kpna2 has been classified as Red List (Low Evidence).
COVID-19 research v0.213 KPNA2 Rebecca Foulger changed review comment from: KPNA2 present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301).
Sources: Literature, Other; to: KPNA2 is present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301).
Sources: Literature, Other
COVID-19 research v0.213 KPNA2 Rebecca Foulger gene: KPNA2 was added
gene: KPNA2 was added to Viral susceptibility. Sources: Literature,Other
Mode of inheritance for gene: KPNA2 was set to Unknown
Publications for gene: KPNA2 were set to 17596301
Added comment: KPNA2 present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301).
Sources: Literature, Other
COVID-19 research v0.212 SH3BP2 Catherine Snow Classified gene: SH3BP2 as Red List (low evidence)
COVID-19 research v0.212 SH3BP2 Catherine Snow Added comment: Comment on list classification: Demoting gene based on expert review
COVID-19 research v0.212 SH3BP2 Catherine Snow Gene: sh3bp2 has been classified as Red List (Low Evidence).
COVID-19 research v0.211 FURIN Rebecca Foulger Publications for gene: FURIN were set to
COVID-19 research v0.210 FURIN Rebecca Foulger Classified gene: FURIN as Amber List (moderate evidence)
COVID-19 research v0.210 FURIN Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber: Although no SNP studies, or potential variants identified yet, recent papers (e.g. PMID:32362314) and preprints have identified a role for Furin protease activity in SARS-CoV-2 entry into human cells. Therefore changes to Furin sequence could potentially alter viral susceptibility.
COVID-19 research v0.210 FURIN Rebecca Foulger Gene: furin has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.209 FURIN Rebecca Foulger commented on gene: FURIN: PMID:32362314. Hoffmann et al., 2020 report that Furin cleaves the SARS-CoV-2 spike protein at the S1/S2 site, and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Therefore furin may be a potential target for therapuetic intervention.
COVID-19 research v0.209 FURIN Rebecca Foulger commented on gene: FURIN: PMID:25974265. Hardes et al., 2015. Furing is required for H7N1 and H5N1 influenza virus infection, probably by cleaving hemagglutinin. Therefore inhibition of Furin is a potential strategy for short-term treatment of acute infectious diseases, including avian influenza.
Monogenic hearing loss v2.18 SLC52A3 Eleanor Williams Tag for-review tag was added to gene: SLC52A3.
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Tag for-review tag was added to gene: SLC52A2.
COVID-19 research v0.209 FURIN Rebecca Foulger commented on gene: FURIN
Hypophosphataemia or rickets v2.5 CLCN5 Ivone Leong Publications for gene: CLCN5 were set to 28383812; 9187673
COVID-19 research v0.209 CD14 Catherine Snow Classified gene: CD14 as Green List (high evidence)
COVID-19 research v0.209 CD14 Catherine Snow Added comment: Comment on list classification: Upgrade to Green based on expert review from Sophie Hambleton
COVID-19 research v0.209 CD14 Catherine Snow Gene: cd14 has been classified as Green List (High Evidence).
COVID-19 research v0.208 ABO Catherine Snow Classified gene: ABO as Green List (high evidence)
COVID-19 research v0.208 ABO Catherine Snow Added comment: Comment on list classification: Upgrade to Green based on expert review
COVID-19 research v0.208 ABO Catherine Snow Gene: abo has been classified as Green List (High Evidence).
Ectodermal dysplasia v1.6 KREMEN1 Catherine Snow Classified gene: KREMEN1 as Amber List (moderate evidence)
Ectodermal dysplasia v1.6 KREMEN1 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber as additional family with ED identified in literature by external reviewer.
Ectodermal dysplasia v1.6 KREMEN1 Catherine Snow Gene: kremen1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.5 KREMEN1 Catherine Snow Publications for gene: KREMEN1 were set to 27049303
COVID-19 research v0.207 SELPLG Sarah Leigh commented on gene: SELPLG: PMID: 30833724 identifies SELPLG (refered to as PSGL1 in the literature) as an HIV restriction factor, SELPLG is induced by interferon-γ in activated CD4+ T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions.
Preprint https://doi.org/10.1101/2020.05.01.073387 report that virion incorporation of SELPLG on SARS-CoV and SARS-CoV-2 pseudovirions blocks S protein-mediated virus attachment and infection of target cells, Suggesting that SELPLG-imprinted non-infectious viral particles could serve as a live attenuated vaccine for SARS-CoV-2 infection.
COVID-19 research v0.207 SELPLG Sarah Leigh gene: SELPLG was added
gene: SELPLG was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: SELPLG was set to Unknown
Publications for gene: SELPLG were set to 19543284; 30833724; doi.org/10.1101/2020.05.01.073387
Review for gene: SELPLG was set to RED
Added comment: In PMID 19543284 SELPLG (refered to as PSGL1 in the literature) is a receptor for 5 of 8 the Enterovirus-71 (EV71) strains. EV71 interaction and viral replication could be inhibited by monoclonal antibodies to SELPLG. The authors concluded that SELPLG-positive leukocytes are involved in the cell tropism and pathogenesis of hand, foot and mouth disease and other EV71-mediated diseases.
Sources: Literature
COVID-19 research v0.206 ACE2 Sarah Leigh changed review comment from: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.; to: Preprint: https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.

Preprint: https://doi.org/10.1101/2020.05.03.074781 uses mCSM-PPI212 mutation effect predictor for protein-protein complex affinity, primarily validated against published experimental ACE2 variant SARS-CoV S-protein affinities to analysis variants from gnomAD. p.Gly326Glu, predicted to enhances ACE2 binding affinity for SARS-CoV-2 S, therefore a potential risk factor for COVID-19. p.Glu37Lys, p.Gly352Val and p.Asp355Asn predicted to reduce ACE2 affinity for SARS-CoV-2 S, therefore potentially protective against COVID-19.
Catecholaminergic polymorphic VT v2.4 CALM3 Eleanor Williams Phenotypes for gene: CALM3 were changed from to ?Ventricular tachycardia, catecholaminergic polymorphic 6, 618782; Long QT syndrome 16,618782
Long QT syndrome v2.6 CALM3 Eleanor Williams Phenotypes for gene: CALM3 were changed from to ?Ventricular tachycardia, catecholaminergic polymorphic 6, 618782; Long QT syndrome 16,618782
Mitochondrial disorders v2.6 QRSL1 Eleanor Williams Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835
COVID-19 research v0.206 CCL5 Sarah Leigh Classified gene: CCL5 as Green List (high evidence)
COVID-19 research v0.206 CCL5 Sarah Leigh Added comment: Comment on list classification: Based on expert review by Sophie Hambleton (Newcastle University)
COVID-19 research v0.206 CCL5 Sarah Leigh Gene: ccl5 has been classified as Green List (High Evidence).
Possible mitochondrial disorder - nuclear genes v1.15 QRSL1 Eleanor Williams Phenotypes for gene: QRSL1 were changed from Mitochondrial cardiomyopathy to Mitochondrial cardiomyopathy; Combined oxidative phosphorylation deficiency 40, 618835
Likely inborn error of metabolism v2.8 QRSL1 Eleanor Williams Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835
Intellectual disability v3.62 TMX2 Eleanor Williams Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Intellectual disability v3.61 SMARCD1 Eleanor Williams Phenotypes for gene: SMARCD1 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot; Coffin-Siris syndrome 11, 618779
Hereditary spastic paraplegia v1.215 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Complex hereditary spastic paraplegia; Spastic paraplegia 82, autosomal recessive #618770 to Complex hereditary spastic paraplegia; Spastic paraplegia 82, autosomal recessive, 618770
Early onset or syndromic epilepsy v2.50 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy; Spastic paraplegia 82, autosomal recessive, 618770
Hereditary spastic paraplegia v1.214 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Complex hereditary spastic paraplegia to Complex hereditary spastic paraplegia; Spastic paraplegia 82, autosomal recessive #618770
COVID-19 research v0.205 ACE2 Sarah Leigh changed review comment from: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.; to: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.
COVID-19 research v0.205 ACE2 Sarah Leigh commented on gene: ACE2
Intellectual disability v3.60 NKAP Eleanor Williams Phenotypes for gene: NKAP were changed from Global developmental delay; Intellectual disability to Global developmental delay; Intellectual disability; Intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type #301039
Intellectual disability v3.59 DLG4 Eleanor Williams Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual disability; Marfanoid habitus; Intellectual developmental disorder 62 #618793
Fetal anomalies v1.59 SUZ12 Eleanor Williams Phenotypes for gene: SUZ12 were changed from Weaver-like overgrowth syndrome to Weaver-like overgrowth syndrome; Imagawa-Matsumoto syndrome #618786
Kabuki syndrome v1.4 PQBP1 Rebecca Foulger Phenotypes for gene: PQBP1 were changed from intellectual disability; long triangular face; bulbous nose; hypoplastic malar region; micrognathia; partial agenesis of corpus callosum; spasticity; contractures to Kabuki-like syndrome; intellectual disability; long triangular face; bulbous nose; hypoplastic malar region; micrognathia; partial agenesis of corpus callosum; spasticity; contractures
Kabuki syndrome v1.3 PQBP1 Rebecca Foulger Classified gene: PQBP1 as Red List (low evidence)
Kabuki syndrome v1.3 PQBP1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Red. Gene was added to the panel and rated Red by Cristina Dias. 1 individual in PMID:30244542 with PQBP1 hemizygous variant and Kabuki-like dysmorphic facial features. Therefore Red rating appropriate awaiting further cases that expand the phenotypic spectrum of PQBP1 disorders.
Kabuki syndrome v1.3 PQBP1 Rebecca Foulger Gene: pqbp1 has been classified as Red List (Low Evidence).
Kabuki syndrome v1.2 PQBP1 Rebecca Foulger commented on gene: PQBP1
COVID-19 research v0.205 CCL5 Sarah Leigh reviewed gene: CCL5: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.02.20084673; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.205 CCR5 Sarah Leigh edited their review of gene: CCR5: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673
COVID-19 research v0.205 IL6 Sarah Leigh Classified gene: IL6 as Green List (high evidence)
COVID-19 research v0.205 IL6 Sarah Leigh Gene: il6 has been classified as Green List (High Evidence).
COVID-19 research v0.204 IL6 Sarah Leigh edited their review of gene: IL6: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673
Intellectual disability v3.58 CDK8 Eleanor Williams Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748
Congenital myopathy v2.5 FXR1 Eleanor Williams Phenotypes for gene: FXR1 were changed from Congenital multi-minicore myopathy to Congenital multi-minicore myopathy; ?Myopathy, congenital proximal, with minicore lesions #618823; ?Myopathy, congenital, with respiratory insufficiency and bone fractures #618822
Childhood onset hereditary spastic paraplegia v2.12 PCYT2 Rebecca Foulger Tag for-review tag was added to gene: PCYT2.
Childhood onset hereditary spastic paraplegia v2.12 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Childhood onset hereditary spastic paraplegia v2.12 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Added to panel based on sufficient cases in PMID:31637422 with HSP phenotype. Updated rating to Green following confirmation from Helen Brittain, Genomics England Clinical Team, that phenotype is appropriate for the panel. Added 'for-review' tag so that GLHs can confirm that gene is indeed required for childhood onset panel (as Helen notes: one patient had onset at 16 and mild delay of motor skills).
Childhood onset hereditary spastic paraplegia v2.12 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Childhood onset hereditary spastic paraplegia v2.11 PCYT2 Rebecca Foulger gene: PCYT2 was added
gene: PCYT2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive, 618770
Added comment: PMID:31637422. In 5 patients from 4 unrelated families with autosomal recessive spastic paraplegia-82 (MIM:618770), Vaz et al. (2019) identified homozygous or compound heterozygous mutations in the PCYT2 gene. The variants segregated with the disorder in all families. Functional studies showed reduced (not absent) PYCT2 activity.
Sources: Literature
Adult onset hereditary spastic paraplegia v1.7 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Adult onset hereditary spastic paraplegia v1.7 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as Green for now based on sufficient cases with HSP phenotype in PMID:31637422. Added 'for-review' tag as suggested by Helen Brittain, Genomics England Clinical Team, as this gene requires additional review by GLH as to appropriateness for adult panel.
Adult onset hereditary spastic paraplegia v1.7 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Adult onset hereditary spastic paraplegia v1.6 PCYT2 Rebecca Foulger Tag for-review tag was added to gene: PCYT2.
Adult onset hereditary spastic paraplegia v1.6 PCYT2 Rebecca Foulger gene: PCYT2 was added
gene: PCYT2 was added to Hereditary spastic paraplegia - adult onset. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive, 618770
Added comment: PMID:31637422. In 5 patients from 4 unrelated families with autosomal recessive spastic paraplegia-82 (MIM:618770), Vaz et al. (2019) identified homozygous or compound heterozygous mutations in the PCYT2 gene. The variants segregated with the disorder in all families. Functional studies showed reduced (not absent) PYCT2 activity.
Sources: Literature
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel and rated Green by Konstantinos Varvagiannis. Green rating confirmed by Genomics England Clinical Team.
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Intellectual disability v3.57 PCYT2 Rebecca Foulger Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy to Spastic paraplegia 82, autosomal recessive, 618770; Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
COVID-19 research v0.204 TMPRSS2 Sarah Leigh reviewed gene: TMPRSS2: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.04.075911; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.56 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Intellectual disability v3.56 EXT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Sufficient cases to support causation of MIM:616682, of which ID is a prominent phenotype. Note that I have updated the Mode of Inheritance from AD to AR to match MIM:616682 (and the Genetic epilepsy syndromes panel, #402).
Intellectual disability v3.56 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Intellectual disability v3.55 EXT2 Rebecca Foulger changed review comment from: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).; to: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N variant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30997052. In a 14 year old girl, Gupta et al. (2019) identified compound het missense variants in the EXT2 gene (V373D and T672M), which segregated with the disorder in the family. The patient also carried a maternal heterozygous variant (R454C) in NDST1. She had developmental delay, autism and epilepsy amongst her phenotypes.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30075207. In 2 brothers, born of consanguineous Syrian parents, with MIM:616682 El-Bazzal et al. (2019) identified a homozygous missense mutation in the EXT2 gene (p.Ser4Leu). Psychomotor delay was noted for both at the age of 3 months.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:26246518: In 4 siblings, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly/microcephaly syndrome (MIM:616682), Farhan et al. (2015) identified homozygosity for 2 missense mutations in EXT2 (M87R and R95C). All siblings had moderate ID and a seizure disorder.
Intellectual disability v3.55 EXT2 Rebecca Foulger Phenotypes for gene: EXT2 were changed from Seizures, scoliosis, and macrocephaly syndrome, 616682 to Seizures, scoliosis, and macrocephaly syndrome, 616682; autosomal recessive EXT2-related syndrome
Intellectual disability v3.54 EXT2 Rebecca Foulger Deleted their comment
Intellectual disability v3.54 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.54 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.53 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to 25529582; 26246518; 30997052; 30288735
Intellectual disability v3.52 EXT2 Rebecca Foulger Phenotypes for gene: EXT2 were changed from Exostoses, multiple, type 2, 133701 to Seizures, scoliosis, and macrocephaly syndrome, 616682
Intellectual disability v3.51 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to 25529582
Intellectual disability v3.51 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.51 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.50 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.49 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to
Intellectual disability v3.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707; ID associated with autistic features, seizures, and developmental delay; intellectual disability
Intellectual disability v3.47 POU3F3 Rebecca Foulger Phenotypes for gene: POU3F3 were changed from Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior to Snijders Blok-Fisher syndrome, 618604; Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Intellectual disability v3.46 POLR2A Rebecca Foulger Phenotypes for gene: POLR2A were changed from Global developmental delay; Generalized hypotonia; Feeding difficulties to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, 618603; Global developmental delay; Generalized hypotonia; Feeding difficulties
CAKUT v1.106 GPC3 Ivone Leong Classified gene: GPC3 as Green List (high evidence)
CAKUT v1.106 GPC3 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and literature there is enough evidence to support a gene-disease association. Therefore, this gene has been given Green status.
CAKUT v1.106 GPC3 Ivone Leong Gene: gpc3 has been classified as Green List (High Evidence).
CAKUT v1.105 GPC3 Ivone Leong Publications for gene: GPC3 were set to
Intellectual disability v3.45 PHF21A Rebecca Foulger Added comment: Comment on phenotypes: Potocki-Shaffer syndrome (MIM:601224) is a contiguous gene deletion syndrome involving genes on chromosome 11p11.2.
Intellectual disability v3.45 PHF21A Rebecca Foulger Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725 to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Intellectual disability v3.44 PHF21A Rebecca Foulger Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Intellectual disability v3.43 MSL3 Rebecca Foulger Phenotypes for gene: MSL3 were changed from Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; Basilicata-Akhtar syndrome, 301032
CAKUT v1.104 HOXA13 Ivone Leong Classified gene: HOXA13 as Green List (high evidence)
CAKUT v1.104 HOXA13 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and available literature there is enough evidence to support a gene-disease association. Therefore, this gene has been given a Green status.
CAKUT v1.104 HOXA13 Ivone Leong Gene: hoxa13 has been classified as Green List (High Evidence).
CAKUT v1.103 HOXA13 Ivone Leong Publications for gene: HOXA13 were set to
CAKUT v1.102 LIFR Ivone Leong Classified gene: LIFR as Green List (high evidence)
CAKUT v1.102 LIFR Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and the evidence there is enough evidence to support a gene-disease association. Therefore, this gene has been given Green status.
CAKUT v1.102 LIFR Ivone Leong Gene: lifr has been classified as Green List (High Evidence).
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Tag treatable tag was added to gene: SLC52A2.
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Classified gene: SLC52A2 as Green List (high evidence)
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. More than 3 cases reported in patients with Brown-Vialetto-Van Laere syndrome 2 and variants in this gene. Expert reviewer reports that hearing loss may be the first presentation.
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Gene: slc52a2 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.17 SLC52A2 Eleanor Williams Phenotypes for gene: SLC52A2 were changed from to Brown-Vialetto-Van Laere syndrome 2 #614707
Monogenic hearing loss v2.16 SLC52A2 Eleanor Williams Publications for gene: SLC52A2 were set to
Monogenic hearing loss v2.15 SLC52A2 Eleanor Williams Mode of inheritance for gene: SLC52A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams edited their review of gene: SLC52A2: Changed publications: 22740598, 22864630, 23243084, 24253200; Changed phenotypes: Brown-Vialetto-Van Laere syndrome 2 #614707
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams edited their review of gene: SLC52A2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams commented on gene: SLC52A2: Associated with Brown-Vialetto-Van Laere syndrome 2 #614707 (AR) in OMIM. Early childhood onset of sensorineural deafness is a feature along with bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency.

Numerous cases have been reported with variants in the SLC52A2 gene and Brown-Vialetto-Van Laere syndrome 2:

PMID: 22740598 Johnson et al 2012 - used linkage and exome sequencing to identify a novel mutation (p.G306R (c.916G>A)) in SLC52A2 in an extended Lebanese Brown-Vialetto-Van Laere kindred. The same homozygous mutation was identified in one additional subject from the UK, from 44 screened.

PMID: 22864630 Haack et al 2012 - exome sequencing of a single case with Brown-Vialetto-Van Laere syndrome showed compound heterozygosity for two pathogenic mutations in the SLC52A2 gene. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities.

PMID: 23243084 Ciccolella et al 2013 - 1 case of a severe BVVL patient with two novel compound heterozygous mutations in SLC52A2 (c.155C>T, p.S52F and c.1255G>A, p.G419S). Functional studies show that these variants impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport.

PMID: 24253200 Foley et al 2014 - using exome and sanger sequencing identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy, hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression.
Hypophosphataemia or rickets v2.4 CLCN5 Martina Owens changed review comment from: Variants in this gene cause Dent disease - Oudet et al 1997 (PMID: 9187673) - family with four brothers presenting low molecular weight proteinuria, dramatic hypercalciuria and hypophosphataemic rickets. Morimoto et al 1998 (PMID: 9596078) - all patients had low molecular weight proteinuria (LMWP). LMWP is the pathognomonic finding of Dent disease, therfore possible that these patients will be tested using the Proteinuric renal disease panel. 60% patients with Dent disease have variant in this gene (NB. 15% of Dent patients have variants in the OCRL gene and this gene should be considerd for addition to the Proteinuric renal disease panel).; to: Variants in this gene cause Dent disease - Oudet et al 1997 (PMID: 9187673) - family with four brothers presenting low molecular weight proteinuria, dramatic hypercalciuria and hypophosphataemic rickets. Morimoto et al 1998 (PMID: 9596078) - all patients had low molecular weight proteinuria (LMWP). LMWP is the pathognomonic finding of Dent disease, therfore possible that these patients will be tested using the Proteinuric renal disease panel. 60% patients with Dent disease have variant in this gene (NB. 15% of Dent patients have variants in the OCRL gene and this gene should be considered for addition to the Proteinuric renal disease panel).
CAKUT v1.101 LRP4 Ivone Leong Classified gene: LRP4 as Green List (high evidence)
CAKUT v1.101 LRP4 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. LRP4 is associated with a relevant phenotype in OMIM and Gene2Phenotype, with Gene2Phenotype listing renal agenesis and renal hypoplasia as a phenotype. There are >3 unrelated cases of patients with LRP4 variants who have renal hypoplasia or renal agenesis as a feature. There is also a mouse model. Therefore there is enough evidence to support a gene-disease association for this gene to be Green.
CAKUT v1.101 LRP4 Ivone Leong Gene: lrp4 has been classified as Green List (High Evidence).
CAKUT v1.100 LRP4 Ivone Leong Publications for gene: LRP4 were set to
Monogenic hearing loss v2.14 SLC52A3 Eleanor Williams Phenotypes for gene: SLC52A3 were changed from to Brown-Vialetto-Van Laere syndrome 1 #211530
Monogenic hearing loss v2.13 SLC52A3 Eleanor Williams Publications for gene: SLC52A3 were set to
Monogenic hearing loss v2.12 SLC52A3 Eleanor Williams edited their review of gene: SLC52A3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.12 SLC52A3 Eleanor Williams Tag treatable tag was added to gene: SLC52A3.
Monogenic hearing loss v2.12 SLC52A3 Eleanor Williams Mode of inheritance for gene: SLC52A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.11 SLC52A3 Eleanor Williams Classified gene: SLC52A3 as Green List (high evidence)
Monogenic hearing loss v2.11 SLC52A3 Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported with variants in SLC52A3 in patients Brown-Vialetto-van Laere syndrome. Sensorineural deafness is a feature of this syndrome and often presents first.
Monogenic hearing loss v2.11 SLC52A3 Eleanor Williams Gene: slc52a3 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.10 SLC52A3 Eleanor Williams commented on gene: SLC52A3: Associated with Brown-Vialetto-Van Laere syndrome 1 #211530 (AR) in OMIM, a form of progressive bulbar palsy with sensorineural deafness.

Multiple cases of variants in this gene have been found in patients with Brown-Vialetto-Van Laere syndrome 1:

PMID: 20206331 Green et al 2010 - identified homozygous or compound heterozygous variants in C20orf54 (SLC52A3) in individuals with Brown-Vialetto-Van Laere syndrome from 7 families of European, Pakistani and Arabic ancestry. Nonsense and missense variants were found. Used homozgyosity mapping in the first family and then candidate gene analysis. They also report that 58 cases have been documented in the literature, with the age at onset ranged from infancy to early in the third decade, with the majority presenting in the second decade. Hearing loss preceded the onset of neurological signs in most cases. C20ORF54 is thought to play a role in riboflavin transport.

PMID: 20920669 Johnson et al 2010 - performed exome sequencing in patients with Brown-Vialetto-van Laere syndrome. In one patient in common with Green et al 2010 they found compound heterozygous variants in C20orf54 (patient 2008-410) rather than the homozygous variant Green et al reported (case 4). The results were confirmed by Sanger sequence and the parents were found to each have 1 heterozygous variant. They also report an additional family (DZ) from Eastern Turkey with a homozygous variant in affected individuals.
Intellectual disability v3.42 CNOT3 Rebecca Foulger commented on gene: CNOT3
Intellectual disability v3.42 CNOT3 Rebecca Foulger Mode of inheritance for gene: CNOT3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.41 CNOT3 Rebecca Foulger Publications for gene: CNOT3 were set to 25529582; 28135719
Intellectual disability v3.40 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; intellectual disability, global developmental delay to CNOT3 syndrome; intellectual disability, global developmental delay; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672
Early onset or syndromic epilepsy v2.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; Intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707
COVID-19 research v0.204 ACE2 Rebecca Foulger commented on gene: ACE2: Added 'treatable' tag based on preprint http://biorxiv.org/cgi/content/short/2020.05.07.082230 which suggests that a modified ACE2 peptide could act as a treatment to block the viral receptor forming a complex with ACE2.
COVID-19 research v0.204 ACE2 Rebecca Foulger Tag treatable tag was added to gene: ACE2.
Laterality disorders and isomerism v1.5 NODAL Zornitza Stark reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: None; Publications: 9354794, 19064609; Phenotypes: Heterotaxy, visceral, 5 (MIM#270100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.99 LRP4 Ivone Leong Phenotypes for gene: LRP4 were changed from Cenani-Lenz syndactyly syndrome, MIM# 212780 to Cenani-Lenz syndactyly syndrome, 212780
CAKUT v1.98 LIFR Ivone Leong Publications for gene: LIFR were set to PMID: 28334964
CAKUT v1.97 KMT2D Ivone Leong Classified gene: KMT2D as Green List (high evidence)
CAKUT v1.97 KMT2D Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and review there is enough evidence to support a gene-disease association; therefore, this gene has been given Green status.
CAKUT v1.97 KMT2D Ivone Leong Gene: kmt2d has been classified as Green List (High Evidence).
CAKUT v1.96 KMT2D Ivone Leong Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920 to Kabuki syndrome 1, 147920
CAKUT v1.95 KDM6A Ivone Leong Classified gene: KDM6A as Green List (high evidence)
CAKUT v1.95 KDM6A Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and review there is enough evidence to support a gene-disease association; therefore, this gene has been given Green status.
CAKUT v1.95 KDM6A Ivone Leong Gene: kdm6a has been classified as Green List (High Evidence).
CAKUT v1.94 KDM6A Ivone Leong Mode of inheritance for gene: KDM6A was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.93 KDM6A Ivone Leong Phenotypes for gene: KDM6A were changed from Kabuki syndrome 2, MIM# 300867 to Kabuki syndrome 2, 300867
CAKUT v1.92 JAG1 Ivone Leong Classified gene: JAG1 as Green List (high evidence)
CAKUT v1.92 JAG1 Ivone Leong Gene: jag1 has been classified as Green List (High Evidence).
CAKUT v1.91 JAG1 Ivone Leong Classified gene: JAG1 as No list
CAKUT v1.91 JAG1 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer (Chirag Patel (Genetic Health Queensland)). JAG1 is associated with a relevant disease in OMIM and Gene2Phenotype.

Renal structural involvement for cases of Alagille syndrome caused by variants in the JAG1 gene is well known. Based on the expert review and literature evidence there is enough evidence to support a gene-disease assocation. Therefore this gene has been given Green status.
CAKUT v1.91 JAG1 Ivone Leong Gene: jag1 has been removed from the panel.
CAKUT v1.90 JAG1 Ivone Leong Publications for gene: JAG1 were set to 22105858
Monogenic hearing loss v2.10 SLC52A3 Eleanor Williams gene: SLC52A3 was added
gene: SLC52A3 was added to Hearing loss. Sources: Expert list
Mode of inheritance for gene: SLC52A3 was set to Unknown
Added comment: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust). Sensorineural deafness is the presenting feature in cases presenting after infancy with other neurology a year or 2 later – treatment with Riboflavin can be effective.
Sources: Expert list
Monogenic hearing loss v2.9 SLC52A2 Eleanor Williams changed review comment from: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust)
Sources: Expert list; to: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust). Sensorineural deafness is the presenting feature in cases presenting after infancy with other neurology a year or 2 later – treatment with Riboflavin can be effective.
Sources: Expert list
Monogenic hearing loss v2.9 SLC52A2 Eleanor Williams gene: SLC52A2 was added
gene: SLC52A2 was added to Hearing loss. Sources: Expert list
Mode of inheritance for gene: SLC52A2 was set to Unknown
Added comment: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust)
Sources: Expert list
CAKUT v1.89 JAG1 Ivone Leong Phenotypes for gene: JAG1 were changed from Alagille syndrome 1; OMIM #118450 to Alagille syndrome 1 118450
CAKUT v1.88 JAG1 Ivone Leong Publications for gene: JAG1 were set to PMID: 22105858
CAKUT v1.87 HOXA13 Ivone Leong Phenotypes for gene: HOXA13 were changed from Hand-foot-uterus syndrome, MIM# 140000 to Hand-foot-uterus syndrome, 140000
Fetal anomalies v1.58 EXOC3L2 Rebecca Foulger Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation to Dandy-Walker malformation; Meckel-Gruber-like syndrome
CAKUT v1.86 GREB1L Ivone Leong Classified gene: GREB1L as Green List (high evidence)
CAKUT v1.86 GREB1L Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. GREB1L is associated with a relevant phenotype in OMIM (there are >3 cases described there). Based on the expert reviews and literature there is enough to support gene-disease association, therefore this gene has been given a Green status.
CAKUT v1.86 GREB1L Ivone Leong Gene: greb1l has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 MYO5B Rebecca Foulger commented on gene: MYO5B
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 MYO5B Rebecca Foulger Tag for-review tag was added to gene: MYO5B.
CAKUT v1.85 GREB1L Ivone Leong Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, MIM# 617805 to Renal hypodysplasia/aplasia 3, 617805
CAKUT v1.84 GREB1L Ivone Leong Publications for gene: GREB1L were set to 29100091
COVID-19 research v0.204 SNORA31 Abdelazeem Elhabyan reviewed gene: SNORA31: Rating: ; Mode of pathogenicity: None; Publications: 31806906; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 TICAM1 Abdelazeem Elhabyan reviewed gene: TICAM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22105173,26513235; Phenotypes: Herpes simplex encephalitis predisposition; Mode of inheritance: Other
Early onset or syndromic epilepsy v2.47 NR4A2 Konstantinos Varvagiannis gene: NR4A2 was added
gene: NR4A2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Phenotypes for gene: NR4A2 were set to Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Penetrance for gene: NR4A2 were set to unknown
Review for gene: NR4A2 was set to GREEN
Added comment: Seizures have been reported in at least 6 unrelated individuals with NR4A2 variants (not including cases with contiguous gene deletions spanning also this gene). Please consider inclusion with amber or green rating.
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Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.

Previous reviews for the ID panel:
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In a study of 457 autism families (Feliciano et al. - doi.org/10.1101/516625) the authors provide phenotypic information on a further individual with ASD and ID. This subject (SP0041645 - SPARK cohort) harbored a de novo frameshift variant (p.G231fs using ENST00000409572.1 as reference). Table 2 includes also the individual previously reported by Iossifov et al. who also presented with ASD and ID (11172.p1 - SSC cohort - PMID and details discussed below).
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Recent publications provide several lines of evidence that pathogenic NR4A2 variants cause DD/ID and/or autism spectrum disorder (ASD).

Lévy et al. (PMID: 29770430) summarize the phenotype of 2q24.1 microdeletions spanning either only NR4A2 [2 new patients as well as an individual reported by Reuter et al (PMID: 28544326)] or both NR4A2 and GPD2 (1 patient from this study as well as 2 further from Leppa et al. (PMID: 27569545) and Barge-Schaapveld et al. (PMID: 23554088)]. All these CNVs had occurred as de novo events. Common features included - among others - language impairment (6/6), ID (6/6), ASD (3/4) or abnormal behaviour (4/4).

As the authors note, NR4A2 belongs to a subfamily of highly conserved transcription factors. The gene is involved in several developmental processes, among others in neuronal development. Previous studies have also shown high expression in human fetal brain as well as a role in the development of language-related brain regions.

The absence of CNVs in general population encompassing NR4A2 (and presence of such CNVs spanning GDP2) as well as the minimal deletions confined to NR4A2 suggest that happloinsufficiency of NR4A2 is responsible for the DD/ID/ASD phenotypes. This is also supported by the HI index of 1.28 as well as pLI of 0.99.

Guo et al. (PMID: 30504930) report on a patient with de novo frameshift variant (p.P201Rfs*82) and provide a summary of individuals with de novo missense variants (schematic overview in suppl. fig. S4) previously reported in larger DD/ID/ASD cohorts, namely :

- The DDD study (PMID: 28135719) : subjects DDD4K.00386 (R312Q - https://decipher.sanger.ac.uk/ddd/research-variant/1e7622c3a0ba1b506c5808ccea46e759#overview) and DDD4K.04161 (R289P - https://decipher.sanger.ac.uk/ddd/research-variant/673e8e570d28dd0c5797ddafb22e53eb#overview)

- By Lelieveld et al. (PMID: 27479843) : patient with ID and V307G

- By Iossifov et al. (PMID: 25363768) : subject with ASD and Y275H.

[All these appear to cluster in a region of missense constraint : https://decipher.sanger.ac.uk/gene/NR4A2#overview/protein-info].

NR4A2 is not associated with any phenotype in OMIM, nor in G2P.

The gene is included in gene panels for intellectual disability offered by diagnostic laboratories (incl. Radboudumc).

As a result, it could be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Sources: Literature
Intellectual disability v3.39 NR4A2 Konstantinos Varvagiannis edited their review of gene: NR4A2: Added comment: Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.; Changed publications: https://doi.org/10.1038/s41436-020-0815-4, 31428396, 29770430, 30504930, 28544326, 27569545, 23554088, 28135719, 27479843, 25363768; Changed phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Early onset or syndromic epilepsy v2.47 CUL3 Konstantinos Varvagiannis gene: CUL3 was added
gene: CUL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUL3 were set to 32341456
Phenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496
Penetrance for gene: CUL3 were set to unknown
Review for gene: CUL3 was set to AMBER
Added comment: Epilepsy has been reported in at least 2 relevant individuals in the literature.
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Nakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants.

Features included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.

CUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.

The 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.

While the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.

In OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.

Nakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.

Heterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]

Overall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible.

Studies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are better summarized in denovo-db (after filtering for coding variants):

http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3
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Please consider inclusion in other panels if appropriate (e.g. for ASD).
Sources: Literature
Intellectual disability v3.39 CUL3 Konstantinos Varvagiannis reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32341456; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of cardiovascular system morphology, Abnormality of the palate, Pseudohypoaldosteronism, type IIE - MIM #614496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.204 ITGAM Sophie Hambleton edited their review of gene: ITGAM: Changed rating: AMBER
COVID-19 research v0.204 IL18 Sophie Hambleton edited their review of gene: IL18: Added comment: IL-18 is important in the pathogenesis of HLH (PMID:29326099) and the newly described autoinflammatory state IL18PAP-MAS (PMID: 31874111). Elevated IL-18 levels were detected in patients with COVID although not differentiating severe from mild/moderate disease (MedRxiv preprint https://doi.org/10.1101/2020.03.02.20029975). It is plausible that genetically determined differences in the activity of IL-18 might influence risk of severe COVID-19; Changed rating: AMBER
COVID-19 research v0.204 IL6 Sophie Hambleton reviewed gene: IL6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 IFNL3 Sophie Hambleton reviewed gene: IFNL3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 CD14 Sophie Hambleton reviewed gene: CD14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 CCL5 Sophie Hambleton reviewed gene: CCL5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.11 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Amber List (moderate evidence)
Arthrogryposis v3.11 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Rated as Amber: 2 unrelated families in PMID:30690204 with arthrogryposis amongst their postnatal phenotypes. Further cases required for diagnostic rating.
Arthrogryposis v3.11 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.204 ABO Sophie Hambleton reviewed gene: ABO: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.10 ATP1A2 Rebecca Foulger gene: ATP1A2 was added
gene: ATP1A2 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 30690204
Phenotypes for gene: ATP1A2 were set to arthrogryposis, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency
Added comment: Added to panel based on PMID:30690204 (Monteiro et al., 2020) who describe 3 newborns from 2 unrelated families who died neontally, presenting in utero with fetal hydrops, seizures and polyhydramnios. At birth they had arthrogryposis, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LOF variants in ATP1A2 were found upon WES.
Sources: Literature
Fetal hydrops v1.22 PSAT1 Rebecca Foulger Classified gene: PSAT1 as Red List (low evidence)
Fetal hydrops v1.22 PSAT1 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. Fetal cases in Neu-Laxova syndrome (MIM:616038) in PMID:25152457 and 31903955 but not necessarily hydrops. Therefore rated Red awaiting further cases with hydrops.
Fetal hydrops v1.22 PSAT1 Rebecca Foulger Gene: psat1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.57 PSAT1 Rebecca Foulger Classified gene: PSAT1 as Green List (high evidence)
Fetal anomalies v1.57 PSAT1 Rebecca Foulger Added comment: Comment on list classification: Rated 'probable' for Neu-Laxova syndrome in Gene2Phenotype, but there are sufficient cases from the literature to support causation (6 families in PMID:25152457 and 1 Chinese family in PMID:31903955). Therefore updated rating from Amber to Green: Fetally-relevant phenotype and sufficient evidence.
Fetal anomalies v1.57 PSAT1 Rebecca Foulger Gene: psat1 has been classified as Green List (High Evidence).
Fetal anomalies v1.56 PSAT1 Rebecca Foulger Phenotypes for gene: PSAT1 were changed from NEU-LAXOVA SYNDROME; PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY to Neu-Laxova syndrome 2, 616038; NEU-LAXOVA SYNDROME; PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY
Fetal anomalies v1.55 PSAT1 Rebecca Foulger Publications for gene: PSAT1 were set to
Fetal anomalies v1.54 PSAT1 Rebecca Foulger commented on gene: PSAT1: PMID:31903955 (Ni et al., 2019) report Chinese Neu-Laxova syndrome (NLS) patients from 2 families. Compound het PSAT1 variants R342W and Y70N were found in the proband from family 1. (PHGDH variants were identified in family 2).
Fetal anomalies v1.54 PSAT1 Rebecca Foulger commented on gene: PSAT1: PMID:25152457. Acuna-Hidalgo et al., 2014 report a rare AR disorder with severe malformations leading to prenatal or early postnatal lethality (Neu-Laxova syndrome). They identified variants in PHGDH, PSAT1 and PSPH in individuals with NLS, including 6 families with 3 different missense and frameshift PSAT1 variants which segregated with the disease.
Intellectual disability v3.39 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2 602481 to Migraine, familial hemiplegic, 2 602481; Alternating hemiplegia of childhood 1, 104290
Fetal hydrops v1.21 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Amber List (moderate evidence)
Fetal hydrops v1.21 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Added to panel by Zornitza Stark. Not yet associated with a disorder in Gene2Phenotype. 2 families with Fetal hydrops reported in PMID:30690204 (3 individuals). Therefore phenotype is relevant to panel, and rated Amber awaiting further cases.
Fetal hydrops v1.21 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.20 ATP1A2 Rebecca Foulger commented on gene: ATP1A2
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Amber List (moderate evidence)
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Added to panel with Amber review by Zornitza Stark. Not yet associated with a disorder in Gene2Phenotype. 2 families reported in PMID:30690204 with a fetally-relevant phenotype (including fetal hydrops). Therefore rated Amber awaiting further cases.
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.53 ATP1A2 Rebecca Foulger commented on gene: ATP1A2
COVID-19 research v0.204 HAVCR2 Sarah Leigh Classified gene: HAVCR2 as Green List (high evidence)
COVID-19 research v0.204 HAVCR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 20 families. PMID 30374066 haplotype analysis identified at least 12 distinct chromosome backgrounds within 7 families homozygous for rs184868814, suggestive of recurrant occurrence.
COVID-19 research v0.204 HAVCR2 Sarah Leigh Gene: havcr2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Classified gene: HAVCR2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 20 families. PMID 30374066 haplotype analysis identified at least 12 distinct chromosome backgrounds within 7 families homozygous for rs184868814, suggestive of recurrant occurrence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Gene: havcr2 has been classified as Green List (High Evidence).
Cystic kidney disease v2.17 SEC61A1 Rebecca Foulger Phenotypes for gene: SEC61A1 were changed from interstitial nephritis; chronic kidney disease; cystic kidney disease; Hyperuricemic nephropathy, familial juvenile, 4, 617056 to glomerulocystic kidney disease; interstitial nephritis; chronic kidney disease; cystic kidney disease; Hyperuricemic nephropathy, familial juvenile, 4, 617056
Cystic kidney disease v2.16 SEC61A1 Rebecca Foulger Phenotypes for gene: SEC61A1 were changed from interstitial nephritis; chronic kidney disease; cystic kidney disease; ator) Hyperuricemic nephropathy, familial juvenile, 4, 617056 to interstitial nephritis; chronic kidney disease; cystic kidney disease; Hyperuricemic nephropathy, familial juvenile, 4, 617056
Cystic kidney disease v2.15 SEC61A1 Rebecca Foulger Phenotypes for gene: SEC61A1 were changed from interstitial nephritis; chronic kidney disease; cystic kidney disease to interstitial nephritis; chronic kidney disease; cystic kidney disease; ator) Hyperuricemic nephropathy, familial juvenile, 4, 617056
Cystic kidney disease v2.14 SEC61A1 Rebecca Foulger Mode of inheritance for gene: SEC61A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.13 SEC61A1 Rebecca Foulger Classified gene: SEC61A1 as Amber List (moderate evidence)
Cystic kidney disease v2.13 SEC61A1 Rebecca Foulger Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.12 ALG8 Rebecca Foulger Publications for gene: ALG8 were set to 30135240
Cystic kidney disease v2.11 ALG8 Rebecca Foulger Phenotypes for gene: ALG8 were changed from cystic liver disease; cystic kidney disease to cystic liver disease; cystic kidney disease; Polycystic liver disease 3 with or without kidney cysts, 617874
Cystic kidney disease v2.10 ALG8 Rebecca Foulger Mode of inheritance for gene: ALG8 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.9 ALG8 Rebecca Foulger Classified gene: ALG8 as Green List (high evidence)
Cystic kidney disease v2.9 ALG8 Rebecca Foulger Gene: alg8 has been classified as Green List (High Evidence).
Cystic kidney disease v2.8 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Cystic kidney disease v2.8 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
Cystic kidney disease v2.7 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from cystic liver disease; cystic kidney disease to cystic liver disease; cystic kidney disease; Gillessen-Kaesbach-Nishimura syndrome, 263210
Cystic kidney disease v2.6 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 31395617
Cystic kidney disease v2.5 ALG9 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI to match review by Eleanor Williams.
Cystic kidney disease v2.5 ALG9 Rebecca Foulger Mode of inheritance for gene: ALG9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v1.53 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from AR lethal skeletal dysplasia; ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis to Gillessen-Kaesbach-Nishimura syndrome, 263210; AR lethal skeletal dysplasia; ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis
Primary immunodeficiency or monogenic inflammatory bowel disease v2.167 HAVCR2 Sarah Leigh Phenotypes for gene: HAVCR2 were changed from Tim-3 deficiency; T-cell lymphoma, subcutaneous panniculitis-like, HLH; T-cell lymphoma, subcutaneous panniculitis-like, 618398; Autoinflammatory Disorders to T-cell lymphoma, subcutaneous panniculitis-like, 618398; Tim-3 deficiency; Autoinflammatory Disorders
Severe familial anorexia v1.3 Eleanor Williams List of related panels changed from to
Juvenile dermatomyositis v1.3 Eleanor Williams List of related panels changed from to
Intellectual disability v3.38 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Intellectual disability v3.38 ALG9 Rebecca Foulger Added comment: Comment on list classification: As highlighted by Zornitza Stark, since the last curation review, a number of papers have been published on the ALG9 phenotype, including PMID:26453364 and PMID:28932688 who review the literature and report additional cases. At least 6-7 (of 10/11) patients have developmental delay. Therefore sufficient cases to support causation and have updated rating from Red to Green.
Intellectual disability v3.38 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
COVID-19 research v0.203 ICOSLG Sarah Leigh edited their review of gene: ICOSLG: Changed rating: RED
PHACE(S) syndrome v1.2 Eleanor Williams List of related panels changed from to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.166 ICOSLG Sarah Leigh Classified gene: ICOSLG as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.166 ICOSLG Sarah Leigh Gene: icoslg has been classified as Red List (Low Evidence).
Familial Neural Tube Defects v1.6 Eleanor Williams List of related panels changed from to
Intellectual disability v3.37 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from Congenital disorder of glycosylation, type Il 608776; Gillessen-Kaesbach-Nishimura syndrome 263210 to Developmental delay; Congenital disorder of glycosylation, type Il 608776; Gillessen-Kaesbach-Nishimura syndrome 263210
COVID-19 research v0.203 ICOSLG Sarah Leigh reviewed gene: ICOSLG: Rating: AMBER; Mode of pathogenicity: None; Publications: 30498080, 31532372; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.36 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants (including the 4 new patients reported by PMID:26453364). They also report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had seizures and developmental delay. She had a homozygous variant in ALG9: p.Tyr287Cys.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.165 ICOSLG Sarah Leigh Classified gene: ICOSLG as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.165 ICOSLG Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. One homozygous variant reported in one case of Combined Immunodeficiency. Supportive functional evidence was presented. This variant in this French Canadian case has been reported twice in PMID 30498080 & 31532372.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.165 ICOSLG Sarah Leigh Gene: icoslg has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.203 ZNF341 Sophie Hambleton reviewed gene: ZNF341: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency, recurrent infections, eczema, skeletal abnormalities, hyper-IgE, mucocutaneous candidiasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.36 ALG9 Rebecca Foulger changed review comment from: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.; to: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a 6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.
Fetal anomalies v1.52 ALG9 Rebecca Foulger changed review comment from: Comment on list classification: ALG9 congenital disorder of glycosylation disorder has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.; to: Comment on list classification: ALG9 congenital disorder of glycosylation has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.
Fetal anomalies v1.52 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Fetal anomalies v1.52 ALG9 Rebecca Foulger Added comment: Comment on list classification: ALG9 congenital disorder of glycosylation disorder has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.
Fetal anomalies v1.52 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
COVID-19 research v0.203 XRCC2 Sophie Hambleton reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.164 ICOSLG Sarah Leigh Publications for gene: ICOSLG were set to 32086639; 32048120; 30498080; 31532372
COVID-19 research v0.203 WRAP53 Sophie Hambleton reviewed gene: WRAP53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.203 UBE2T Sophie Hambleton reviewed gene: UBE2T: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.203 TRIM22 Sophie Hambleton reviewed gene: TRIM22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: very early onset inflammatory bowel disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.51 ALG9 Rebecca Foulger Deleted their comment
COVID-19 research v0.203 IFITM3 Sophie Hambleton reviewed gene: IFITM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.51 ALG9 Rebecca Foulger Tag for-review was removed from gene: ALG9.
Fetal anomalies v1.51 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis to AR lethal skeletal dysplasia; ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis
COVID-19 research v0.203 PIK3CG Sophie Hambleton reviewed gene: PIK3CG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.50 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 26453364; 31420886
COVID-19 research v0.203 TP53 Sophie Hambleton reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.49 ALG9 Rebecca Foulger changed review comment from: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero
, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.; to: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.
Fetal anomalies v1.49 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero
, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.
COVID-19 research v0.203 CDC42 Sophie Hambleton reviewed gene: CDC42: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Haemophagocytic lymphohistiocytosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.49 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:25966638 (Tham et al) performed fetal autopsy on 3 affected fetuses who died in utero from 2 unrelated families (from Turkey and Iraq) with Gillessen-Kaesbach-Nishimura syndrome (AR lethal skeletal dysplasia). All patients were homozygous for a splicing variant in ALG9 (NM_024740.2: c.1173+2T>A).
COVID-19 research v0.203 TOP2B Sophie Hambleton reviewed gene: TOP2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31409799; Phenotypes: hypogammglobulinaemia, B cell deficiency, Hoffman syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.203 TNFSF11 Sophie Hambleton reviewed gene: TNFSF11: Rating: GREEN; Mode of pathogenicity: None; Publications: 17632511; Phenotypes: osteopetrosis, osteoclast-poor; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.36 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 15945070; 15148656
Primary immunodeficiency or monogenic inflammatory bowel disease v2.163 ICOSLG Sarah Leigh Publications for gene: ICOSLG were set to 32086639; 32048120; 30498080
Intellectual disability v3.35 ALG9 Rebecca Foulger commented on gene: ALG9
COVID-19 research v0.203 TNFRSF9 Sophie Hambleton reviewed gene: TNFRSF9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency, autoimmunity, lymphoma, EBV predisposition; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.20 ALG9 Rebecca Foulger Classified gene: ALG9 as Amber List (moderate evidence)
Fetal hydrops v1.20 ALG9 Rebecca Foulger Added comment: Comment on list classification: ALG9 added to panel and rated Green by Zornitza Stark. Although there are 3 families from the literature with hydrops, and there is evidence linking congenital disorders of glycosylation to NIHF, the phenotype is inconsistent. In PMID:26453364, 1/10 patients was reported with hydrops: 3 cousins did not have Hydrops reported despite harbouring the same p.E530K variant. PMID:31420886 report 3/15 ALG9 families with NIHF. Therefore rated Amber awaiting clinical review.
Fetal hydrops v1.20 ALG9 Rebecca Foulger Gene: alg9 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.203 TMPRSS2 Sophie Hambleton reviewed gene: TMPRSS2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Fetal hydrops v1.19 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. Paitient IV:3/patient4 (a male cousin of the index patient) presented with nonimmune hydrops fetalis diagnosed by fetal US at 28 weeks, and a novel homozygous variant p.E350K in the ALG9 gene.
Fetal hydrops v1.19 ALG9 Rebecca Foulger commented on gene: ALG9
COVID-19 research v0.203 TGFBR2 Sophie Hambleton reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15731757, 16928994, 24577266; Phenotypes: Loeys Dietz syndrome, arterial aneurysms, atopy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.203 TGFBR1 Sophie Hambleton reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15731757, 16928994, 24577266; Phenotypes: Loeys Dietz syndrome, arterial aneurysms, atopy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.49 ALG9 Rebecca Foulger Tag for-review tag was added to gene: ALG9.
Fetal anomalies v1.49 ALG9 Rebecca Foulger Classified gene: ALG9 as Amber List (moderate evidence)
Fetal anomalies v1.49 ALG9 Rebecca Foulger Added comment: Comment on list classification: Inborn errors of glycosylation can be a cause of non‐immune hydrops fetalis. Although G2P has a 'probable' GDA rating, there is sufficient evidence to link ALG9 to a glycosylation disorder. Approx 20% of cases show non-immune hydrops fetalis (NIHF). In PMID:26453364, 1/10 patients had NIHF: the patient was one of 4 patients within a consanguineous family and hydrops was not reported for the other 3 cousins. 3/15 ALG9 families reported with hydrops in PMID:31420886. Since phenotype is inconsistent, have kept rating as Amber awaiting further clinical review as to whether there are sufficient cases for inclusion on Fetal anomalies panel.
Fetal anomalies v1.49 ALG9 Rebecca Foulger Gene: alg9 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.203 TGFB1 Sophie Hambleton reviewed gene: TGFB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: infantile-onset inflammatory bowel disease, epilepsy, brain atrophy, posterior leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.48 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to
Fetal anomalies v1.47 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from ALG9-CDG to ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis
Fetal anomalies v1.46 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:31420886 Makhamreh et al., 2020 provide a literature review of Nonimmune hydrops fetalis (NIHF) and congenital disorders of glycosylation. 3/15 families had NIHF and ALG9 variants (20%). Full text unavailable at time of curation.
COVID-19 research v0.203 TFRC Sophie Hambleton reviewed gene: TFRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642240; Phenotypes: combined immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.203 TCIRG1 Sophie Hambleton reviewed gene: TCIRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10888887; Phenotypes: infantile osteopetrosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.46 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. Patient IV:3/patient4 (a male cousin of the index patient) presented with nonimmune hydrops fetalis diagnosed by fetal US at 28 weeks, and a novel homozygous variant p.E350K in the ALG9 gene. Table 2 doesn't list Hydrops in any of the previous patients.
COVID-19 research v0.203 IL2RB Sarah Leigh Classified gene: IL2RB as Green List (high evidence)
COVID-19 research v0.203 IL2RB Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 5 unrelated families (two families with the same variant had shared ethnic heritage PMID 31040185).
COVID-19 research v0.203 IL2RB Sarah Leigh Gene: il2rb has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Classified gene: IL2RB as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 5 unrelated families (two families with the same variant had shared ethnic heritage PMID 31040185).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Gene: il2rb has been classified as Green List (High Evidence).
COVID-19 research v0.202 STN1 Sophie Hambleton reviewed gene: STN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27432940; Phenotypes: syndromic bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.202 SRP72 Sophie Hambleton reviewed gene: SRP72: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541560; Phenotypes: aplastic anaemia, myelodysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.202 IL6R Sarah Leigh Classified gene: IL6R as Green List (high evidence)
COVID-19 research v0.202 IL6R Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases, together with supportive functional studies.
COVID-19 research v0.202 IL6R Sarah Leigh Gene: il6r has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Classified gene: IL6R as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases, together with supportive functional studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Gene: il6r has been classified as Green List (High Evidence).
COVID-19 research v0.201 SRP54 Sophie Hambleton reviewed gene: SRP54: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: severe congenital neutropenia, Shwachman-Diamond syndrome, exocrine pancreatic insufficiency, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset dystonia, chorea or related movement disorder v1.4 WDR34 Catherine Snow commented on gene: WDR34
Childhood onset dystonia, chorea or related movement disorder v1.4 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Skeletal ciliopathies v1.3 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Skeletal ciliopathies v1.3 WDR34 Catherine Snow commented on gene: WDR34
Rare multisystem ciliopathy disorders v1.124 WDR34 Catherine Snow commented on gene: WDR34
Rare multisystem ciliopathy disorders v1.124 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Intellectual disability v3.35 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Intellectual disability v3.35 WDR34 Catherine Snow commented on gene: WDR34
Clefting v2.3 WDR34 Catherine Snow commented on gene: WDR34
Clefting v2.3 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
DDG2P v2.5 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
DDG2P v2.5 WDR34 Catherine Snow commented on gene: WDR34
Fetal anomalies v1.46 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Fetal anomalies v1.46 WDR34 Catherine Snow commented on gene: WDR34
Skeletal dysplasia v2.7 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Skeletal dysplasia v2.7 WDR34 Catherine Snow commented on gene: WDR34
Ductal plate malformation v1.10 WDR34 Catherine Snow commented on gene: WDR34
Ductal plate malformation v1.10 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
COVID-19 research v0.201 SNX10 Sophie Hambleton reviewed gene: SNX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22499339, 23280965, 28592808; Phenotypes: infantile osteopetrosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.5 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Limb disorders v2.5 WDR34 Catherine Snow commented on gene: WDR34
Thoracic dystrophies v1.7 WDR34 Catherine Snow commented on gene: WDR34
Thoracic dystrophies v1.7 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
COVID-19 research v0.201 SNORA31 Sophie Hambleton reviewed gene: SNORA31: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: herpes simplex encephalitis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.5 WDR60 Catherine Snow commented on gene: WDR60
Limb disorders v2.5 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Thoracic dystrophies v1.7 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Thoracic dystrophies v1.7 WDR60 Catherine Snow commented on gene: WDR60
Primary immunodeficiency or monogenic inflammatory bowel disease v2.160 IL6R Sarah Leigh Phenotypes for gene: IL6R were changed from Hyper-IgE; Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features to [Interleukin 6, serum level of, QTL] 614752; [Interleukin-6 receptor, soluble, serum level of, QTL] 614689; Hyper-IgE; Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features
Skeletal ciliopathies v1.3 WDR60 Catherine Snow commented on gene: WDR60
Skeletal ciliopathies v1.3 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Renal ciliopathies v1.15 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Renal ciliopathies v1.15 WDR60 Catherine Snow commented on gene: WDR60
Rare multisystem ciliopathy disorders v1.124 WDR60 Catherine Snow commented on gene: WDR60
Rare multisystem ciliopathy disorders v1.124 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Intellectual disability v3.35 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Intellectual disability v3.35 WDR60 Catherine Snow commented on gene: WDR60
Clefting v2.3 WDR60 Catherine Snow commented on gene: WDR60
Clefting v2.3 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
DDG2P v2.5 WDR60 Catherine Snow commented on gene: WDR60
DDG2P v2.5 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Fetal anomalies v1.46 WDR60 Catherine Snow commented on gene: WDR60
Fetal anomalies v1.46 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Unexplained young onset end-stage renal disease v1.10 WDR60 Catherine Snow commented on gene: WDR60
Unexplained young onset end-stage renal disease v1.10 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Skeletal dysplasia v2.7 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Skeletal dysplasia v2.7 WDR60 Catherine Snow commented on gene: WDR60
Neurological ciliopathies v1.7 WDR63 Catherine Snow Tag new-gene-name tag was added to gene: WDR63.
Neurological ciliopathies v1.7 WDR63 Catherine Snow commented on gene: WDR63
Rare multisystem ciliopathy disorders v1.124 WDR63 Catherine Snow Tag new-gene-name tag was added to gene: WDR63.
Rare multisystem ciliopathy disorders v1.124 WDR63 Catherine Snow commented on gene: WDR63
Rare anaemia v1.4 C15orf41 Catherine Snow commented on gene: C15orf41
Rare anaemia v1.4 C15orf41 Catherine Snow Tag new-gene-name tag was added to gene: C15orf41.
Cytopenias and congenital anaemias v1.73 C15orf41 Catherine Snow Tag new-gene-name tag was added to gene: C15orf41.
Cytopenias and congenital anaemias v1.73 C15orf41 Catherine Snow commented on gene: C15orf41
Renal ciliopathies v1.15 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Neurological ciliopathies v1.7 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Ophthalmological ciliopathies v1.4 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Rare multisystem ciliopathy disorders v1.124 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Cerebral vascular malformations v2.4 MRVI1 Catherine Snow Tag new-gene-name tag was added to gene: MRVI1.
Renal ciliopathies v1.15 KIAA0556 Catherine Snow commented on gene: KIAA0556
Neurological ciliopathies v1.7 KIAA0556 Catherine Snow commented on gene: KIAA0556
Ophthalmological ciliopathies v1.4 KIAA0556 Catherine Snow commented on gene: KIAA0556
Rare multisystem ciliopathy disorders v1.124 KIAA0556 Catherine Snow commented on gene: KIAA0556
Cerebral vascular malformations v2.4 MRVI1 Catherine Snow commented on gene: MRVI1
Intellectual disability v3.35 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Early onset or syndromic epilepsy v2.47 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Fetal hydrops v1.19 AHCY Rebecca Foulger Phenotypes for gene: AHCY were changed from Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; S-adenosylhomocysteine hydrolase deficiency; AHCY deficiency to non-immune hydrops; Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; S-adenosylhomocysteine hydrolase deficiency; AHCY deficiency
Early onset or syndromic epilepsy v2.47 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to AMBER
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Intellectual disability v3.35 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to GREEN
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature