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Skeletal muscle channelopathy v1.24 ATP1A2 Eleanor Williams Added comment: Comment on list classification: Leaving rating as Green but with a recommendation of a red rating following GMS review, as there is only one case reported associated with a skeletal muscle phenotype.
Skeletal muscle channelopathy v1.24 ATP1A2 Eleanor Williams Gene: atp1a2 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.23 ATP1A2 Eleanor Williams Tag Q2_21_rating tag was added to gene: ATP1A2.
Skeletal muscle channelopathy v1.23 ATP1A2 Eleanor Williams Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2, 602481; Alternating hemiplegia of childhood 1, 104290; Hypokalaemic periodic paralysis to hypokalaemic periodic paralysis MONDO:0008223
Skeletal muscle channelopathy v1.22 ATP1A2 Eleanor Williams Publications for gene: ATP1A2 were set to 30423015; 15286158; 18056581
Skeletal muscle channelopathy v1.21 ATP1A2 Eleanor Williams reviewed gene: ATP1A2: Rating: RED; Mode of pathogenicity: None; Publications: 30423015; Phenotypes: hypokalaemic periodic paralysis MONDO:0008223; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Amber List (moderate evidence)
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Following confirmation from the Genomics England clinical team that progressive microcephaly (to the severe range) is within scope of this panel, recommending a green rating for this gene at the next review.
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.205 MPLKIP Ivone Leong Phenotypes for gene: MPLKIP were changed from Trichothiodystrophy 4, nonphotosensitive, OMIM:234050; microcephaly (disease), MONDO:0001149 to microcephaly (disease), MONDO:0001149
Severe microcephaly v2.204 MPLKIP Ivone Leong Classified gene: MPLKIP as Amber List (moderate evidence)
Severe microcephaly v2.204 MPLKIP Ivone Leong Gene: mplkip has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.203 MPLKIP Ivone Leong gene: MPLKIP was added
gene: MPLKIP was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MPLKIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPLKIP were set to 25655951; 25290684; 26518168; 25606444; 26880286; 29421601; 30580289; 30598092; 16977596; 33043633; 33729667
Phenotypes for gene: MPLKIP were set to Trichothiodystrophy 4, nonphotosensitive, OMIM:234050; microcephaly (disease), MONDO:0001149
Review for gene: MPLKIP was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Microcephaly has been reported for 6/20 cases (2 cases <-3SD), growth retardation 15/20 and 7/20 had gonadal dysfunction. There is not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.162 MPLKIP Ivone Leong Phenotypes for gene: MPLKIP were changed from Non-photosensitive trichothiodystrophy 4; Trichothiodystrophy, nonphotosensitive to Trichothiodystrophy 4, nonphotosensitive, OMIM:234050
White matter disorders and cerebral calcification - childhood onset v1.161 MPLKIP Ivone Leong commented on gene: MPLKIP: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is no reported cases of this gene associated with white matter changes, therefore, it is recommended that this gene be demoted to Red.
White matter disorders and cerebral calcification - childhood onset v1.161 MPLKIP Ivone Leong Deleted their comment
White matter disorders and cerebral calcification - childhood onset v1.161 MPLKIP Ivone Leong reviewed gene: MPLKIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - childhood onset v1.161 MPLKIP Ivone Leong Tag Q2_21_rating tag was added to gene: MPLKIP.
Tag Q2_21_expert_review tag was added to gene: MPLKIP.
White matter disorders and cerebral calcification - childhood onset v1.161 MPLKIP Ivone Leong Publications for gene: MPLKIP were set to 25655951; 25290684; 26518168; 25606444; 26880286; 2942160; 30580289; 30598092; 16977596; 33043633; 33729667
White matter disorders and cerebral calcification - childhood onset v1.160 MPLKIP Ivone Leong Publications for gene: MPLKIP were set to 25655951
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 PLG Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: PLG.
Paediatric motor neuronopathies v1.62 AR_CAG Dmitrijs Rots STR: AR_CAG was added
STR: AR_CAG was added to Paediatric motor neuronopathies. Sources: Literature
Mode of inheritance for STR: AR_CAG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for STR: AR_CAG were set to spinal and bulbar muscular atrophy; gynecomastia; muscular weakness
Penetrance for STR: AR_CAG were set to Complete
Review for STR: AR_CAG was set to GREEN
STR: AR_CAG was marked as current diagnostic
Added comment: Sources: Literature
Paediatric motor neuronopathies v1.62 AR Dmitrijs Rots reviewed gene: AR: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: SBMA; 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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 CSF2 Boaz Palterer gene: CSF2 was added
gene: CSF2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CSF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSF2 were set to 33349924
Phenotypes for gene: CSF2 were set to Behcet-like disease; Pathergy
Penetrance for gene: CSF2 were set to unknown
Mode of pathogenicity for gene: CSF2 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: CSF2 was set to RED
Added comment: Rösler et al. described a kindred with two patients affected by a Behcet-like disease characterized by marked pathergy and absent inflammation. They identified a heterozygous variant in the GM-CSF gene CSF2 (c.130A>C, p.N44H) resulting in disruption of an N-glycosylation site. They show that de-glycosylated GM-CSF enhances STAT-5 phosphorylation, and therefore the variant acts as a gain-of-function.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 LRRC32 Boaz Palterer gene: LRRC32 was added
gene: LRRC32 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to Unknown
Publications for gene: LRRC32 were set to 34059789
Phenotypes for gene: LRRC32 were set to Common variable immunodeficiency; Enteropathy; Lymphopenia; Reduced Tregs
Penetrance for gene: LRRC32 were set to unknown
Review for gene: LRRC32 was set to RED
Added comment: Lehmkuhl et al. described two patients with immune dysregulation and mutations of LRRC32. Both patients carried two rare variants, however, patient 1 has both variants in cis, while patient 2 was a compound heterozygote. Reduced protein expression ex-vivo was demonstrated. Conditional mice KO model recapitulated the phenotype.
Sources: Literature
Inherited white matter disorders v1.118 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to MIM#270800
Inherited white matter disorders v1.117 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from to Spastic paraplegia 5A, autosomal recessive, OMIM:270800
Leukodystrophy, adult onset v1.15 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to 24117163; 19439420; 19187859
Leukodystrophy, adult onset v1.14 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
Leukodystrophy, adult onset v1.14 CYP7B1 Arina Puzriakova Added comment: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether the phenotype is appropriate and there is enough potential clinical value to rate as Green on this panel.
Leukodystrophy, adult onset v1.14 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
Leukodystrophy, adult onset v1.13 CYP7B1 Arina Puzriakova reviewed gene: CYP7B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19187859, 19439420, 24117163; Phenotypes: Spastic paraplegia 5A, autosomal recessive , OMIM:270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.159 CYP7B1 Arina Puzriakova changed review comment from: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.; to: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether the phenotype is appropriate and there is enough potential clinical value to rate as Green on this panel.
Leukodystrophy, adult onset v1.13 CYP7B1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: CYP7B1.
White matter disorders and cerebral calcification - childhood onset v1.159 CYP7B1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: CYP7B1.
White matter disorders and cerebral calcification - childhood onset v1.159 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to MIM#270800
White matter disorders and cerebral calcification - childhood onset v1.158 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
White matter disorders and cerebral calcification - childhood onset v1.158 CYP7B1 Arina Puzriakova Added comment: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.
White matter disorders and cerebral calcification - childhood onset v1.158 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.157 CYP7B1 Arina Puzriakova reviewed gene: CYP7B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19187859, 19439420, 24117163; Phenotypes: Spastic paraplegia 5A, autosomal recessive , OMIM:270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.157 KIF5A Ivone Leong Tag Q2_21_rating tag was added to gene: KIF5A.
White matter disorders and cerebral calcification - childhood onset v1.157 KIF5A Ivone Leong Classified gene: KIF5A as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.157 KIF5A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.157 KIF5A Ivone Leong Gene: kif5a has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia v1.226 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to Tsaousidou et al. (2008) i
Hereditary spastic paraplegia, childhood onset v2.40 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive, 270800 to Spastic paraplegia 5A, autosomal recessive, OMIM:270800
Hereditary spastic paraplegia v1.225 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
Leukodystrophy, adult onset v1.13 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive, MIM# 270800 to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
White matter disorders and cerebral calcification - childhood onset v1.156 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
Intellectual disability v3.1115 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive 270800 to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
White matter disorders and cerebral calcification - childhood onset v1.155 KIF5A Ivone Leong Phenotypes for gene: KIF5A were changed from Myoclonus, intractable, neonatal, MIM# 617235 to Myoclonus, intractable, neonatal, OMIM:617235
Optic neuropathy v2.43 ISCA2 Ivone Leong Classified gene: ISCA2 as Amber List (moderate evidence)
Optic neuropathy v2.43 ISCA2 Ivone Leong Gene: isca2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.42 ISCA2 Ivone Leong gene: ISCA2 was added
gene: ISCA2 was added to Optic neuropathy. Sources: Literature
Q2_21_rating tags were added to gene: ISCA2.
Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA2 were set to 25539947; 29297947; 29122497; 29359243
Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4, OMIM:616370; optic atrophy, MONDO:0003608
Review for gene: ISCA2 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There are >3 unrelated cases. Patients usually present with a triad of neurodevelopmental regression, nystagmus with optic atrophy, and diffuse white matter disease. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Intellectual disability v3.1114 CYP7B1 Arina Puzriakova Mode of inheritance for gene: CYP7B1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1113 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
Intellectual disability v3.1113 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.154 ISCA2 Ivone Leong Classified gene: ISCA2 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.154 ISCA2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene is also Green on the Inherited white matter disorders (Version 1.113) panel. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.154 ISCA2 Ivone Leong Gene: isca2 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.153 ISCA2 Ivone Leong Tag founder-effect tag was added to gene: ISCA2.
Tag Q2_21_rating tag was added to gene: ISCA2.
Inherited white matter disorders v1.116 CNTNAP1 Arina Puzriakova Classified gene: CNTNAP1 as Green List (high evidence)
Inherited white matter disorders v1.116 CNTNAP1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green - sufficient cases of white matter disease from unrelated families to warrant a Green rating.

At least 10 unrelated families reported in literature (PMIDs: 28374019; 29511323; 29882456) . Brain imaging in all affected patients shows marked brain hypomyelination/demyelination, as well as variably reduced white matter volume and cerebral atrophy.
Inherited white matter disorders v1.116 CNTNAP1 Arina Puzriakova Gene: cntnap1 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.153 CNTNAP1 Arina Puzriakova changed review comment from: Comment on list classification: There are sufficient cases of white matter defects from unrelated families to warrant a Green rating at the next GMS panel update.; to: Comment on list classification: There are sufficient cases of white matter disease from unrelated families to warrant a Green rating at the next GMS panel update.
Inherited white matter disorders v1.115 CNTNAP1 Arina Puzriakova Publications for gene: CNTNAP1 were set to 29882456
Inherited white matter disorders v1.114 CNTNAP1 Arina Puzriakova Phenotypes for gene: CNTNAP1 were changed from to Hypomyelinating neuropathy, congenital, 3, OMIM:618186
White matter disorders and cerebral calcification - childhood onset v1.153 CNTNAP1 Arina Puzriakova Phenotypes for gene: CNTNAP1 were changed from to Hypomyelinating neuropathy, congenital, 3, OMIM:618186
White matter disorders and cerebral calcification - childhood onset v1.152 CNTNAP1 Arina Puzriakova Publications for gene: CNTNAP1 were set to 29882456
White matter disorders and cerebral calcification - childhood onset v1.151 CNTNAP1 Arina Puzriakova Classified gene: CNTNAP1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.151 CNTNAP1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of white matter defects from unrelated families to warrant a Green rating at the next GMS panel update.
White matter disorders and cerebral calcification - childhood onset v1.151 CNTNAP1 Arina Puzriakova Gene: cntnap1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.150 CNTNAP1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: CNTNAP1.
White matter disorders and cerebral calcification - childhood onset v1.150 CNTNAP1 Arina Puzriakova reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29511323, 29882456; Phenotypes: Hypomyelinating neuropathy, congenital, 3, OMIM:618186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.150 ISCA2 Ivone Leong Phenotypes for gene: ISCA2 were changed from to Multiple mitochondrial dysfunctions syndrome 4, OMIM:616370
White matter disorders and cerebral calcification - childhood onset v1.149 CLPP Ivone Leong changed review comment from: Comment on publications: PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families (1 - 3), with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.; to: Comment on publications: PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families, with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.
White matter disorders and cerebral calcification - childhood onset v1.149 CLPP Ivone Leong Added comment: Comment on publications: PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families (1 - 3), with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.
White matter disorders and cerebral calcification - childhood onset v1.149 CLPP Ivone Leong Publications for gene: CLPP were set to 27899912
White matter disorders and cerebral calcification - childhood onset v1.148 APOPT1 Arina Puzriakova commented on gene: APOPT1: Added new-gene-name tag, new approved HGNC gene symbol for APOPT1 is COA8
White matter disorders and cerebral calcification - childhood onset v1.148 APOPT1 Arina Puzriakova Tag new-gene-name tag was added to gene: APOPT1.
White matter disorders and cerebral calcification - childhood onset v1.148 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
White matter disorders and cerebral calcification - childhood onset v1.147 APOPT1 Arina Puzriakova Classified gene: APOPT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.147 APOPT1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of white matter disease from unrelated families to warrant a Green rating at the next GMS panel update.
White matter disorders and cerebral calcification - childhood onset v1.147 APOPT1 Arina Puzriakova Gene: apopt1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.146 APOPT1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: APOPT1.
White matter disorders and cerebral calcification - childhood onset v1.146 APOPT1 Arina Puzriakova reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.165 APOPT1 Arina Puzriakova Publications for gene: APOPT1 were set to
Paediatric or syndromic cardiomyopathy v1.43 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Mitochondrial disorders v2.40 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Monogenic hearing loss v2.164 APOPT1 Arina Puzriakova Mode of inheritance for gene: APOPT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1112 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Monogenic hearing loss v2.163 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial Complex IV Deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Likely inborn error of metabolism v2.140 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Possible mitochondrial disorder, nuclear genes v1.46 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Undiagnosed metabolic disorders v1.460 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Mitochondrial disorder with complex IV deficiency v1.12 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Inherited white matter disorders v1.113 LAMB1 Arina Puzriakova Publications for gene: LAMB1 were set to 23472759; 17525174; 25925986
White matter disorders and cerebral calcification - childhood onset v1.146 LAMB1 Arina Puzriakova Publications for gene: LAMB1 were set to 25925986; 17525174; 23472759
White matter disorders and cerebral calcification - childhood onset v1.145 LAMB1 Arina Puzriakova reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23472759, 25925986, 29888467; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.25 PIGB Dmitrijs Rots gene: PIGB was added
gene: PIGB was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to intellectual disability; developmental delay; epilepsy; axonal neuropathy
Penetrance for gene: PIGB were set to Complete
Review for gene: PIGB was set to GREEN
gene: PIGB was marked as current diagnostic
Added comment: Murakami et al., reported 10 cases with biallelic PIGB variants with complex and severe phenotype, of whom 4 had peripheral neuropathy.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.145 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, 615191 to Lissencephaly 5, OMIM:615191; Cystic leukoencephalopathy
Intellectual disability v3.1111 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from COBBLESTONE BRAIN MALFORMATION WITHOUT MUSCULAR OR OCULAR ABNORMALITIES to Lissencephaly 5, OMIM:615191
Inherited white matter disorders v1.112 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, 615191 to Lissencephaly 5, OMIM:615191
Leukodystrophy, adult onset v1.12 LAMB1 Arina Puzriakova Classified gene: LAMB1 as Red List (low evidence)
Leukodystrophy, adult onset v1.12 LAMB1 Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently only a single adult-onset case of leukoencephalopathy reported (PMID: 32548278). Additional cases required prior to inclusion on this panel. All other publications to date report congenital or infantile- to childhood-onset leukoencephalopathy.
Leukodystrophy, adult onset v1.12 LAMB1 Arina Puzriakova Gene: lamb1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.144 CLPP Ivone Leong Phenotypes for gene: CLPP were changed from Perrault syndrome 3, MIM# 614129 to Perrault syndrome 3, OMIM:614129
Hydrocephalus v2.105 SMARCC1 Arina Puzriakova commented on gene: SMARCC1: Penetrance for gene SMARCC1 was set from None to Incomplete
Fetal anomalies v1.674 SMARCC1 Arina Puzriakova commented on gene: SMARCC1: Penetrance for gene SMARCC1 was set from None to Incomplete
Rare anaemia v1.23 SLC19A1 Arina Puzriakova Phenotypes for gene: SLC19A1 were changed from Megaloblastic anemia, folate-responsive, MIM# 601775 to Megaloblastic anemia, folate-responsive, OMIM:601775
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Classified gene: SLC19A1 as Red List (low evidence)
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as only a single case reported at this time. Additional cases required to validate pathogenicity of variants in this gene.
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Gene: slc19a1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Classified gene: SPI1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (6) presenting a relevant phenotype, supported by some functional data (PMID: 33951726). However, only able to access the publication abstract at this time - Rating Amber with a watchlist tag until the full text becomes available (on 2022-01-05)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Gene: spi1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.422 SPI1 Arina Puzriakova Phenotypes for gene: SPI1 were changed from agammaglobulinemia to Agammaglobulinemia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SPI1 Arina Puzriakova Tag watchlist tag was added to gene: SPI1.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Tag watchlist tag was added to gene: PDCD6IP.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Classified gene: PDCD6IP as Amber List (moderate evidence)
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Gene: pdcd6ip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.; to: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.; to: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.
Severe microcephaly v2.201 POGZ Arina Puzriakova Publications for gene: POGZ were set to 26942287
Severe microcephaly v2.200 POGZ Arina Puzriakova Tag Q2_21_rating tag was added to gene: POGZ.
Severe microcephaly v2.200 POGZ Arina Puzriakova Classified gene: POGZ as Amber List (moderate evidence)
Severe microcephaly v2.200 POGZ Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Microcephaly is a variable feature (reported in at least 14/31 individuals) but severity is not stated in most cases. However, this can be a presenting feature of the disorder and there are sufficient cases from unrelated families to warrant a Green rating on this panel.
Severe microcephaly v2.200 POGZ Arina Puzriakova Gene: pogz has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1110 POGZ Arina Puzriakova Phenotypes for gene: POGZ were changed from INTELLECTUAL DISABILITY to White-Sutton syndrome, OMIM:616364
Intellectual disability v3.1109 POGZ Arina Puzriakova Publications for gene: POGZ were set to 25533962
Severe microcephaly v2.199 POGZ Arina Puzriakova Phenotypes for gene: POGZ were changed from White-Sutton syndrome, MIM# 616364 to White-Sutton syndrome, OMIM:616364
Arthrogryposis v3.104 EBP Arina Puzriakova Phenotypes for gene: EBP were changed from Chondrodysplasia punctata, X-linked dominant, MIM# 302960 to Chondrodysplasia punctata, X-linked dominant, OMIM:302960
Arthrogryposis v3.103 EBP Arina Puzriakova Mode of inheritance for gene: EBP 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)
Arthrogryposis v3.102 EBP Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: EBP.
Arthrogryposis v3.102 EBP Arina Puzriakova Classified gene: EBP as Amber List (moderate evidence)
Arthrogryposis v3.102 EBP Arina Puzriakova Added comment: Comment on list classification: EBP will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.

Flexion contractures may occur is a subset of patients with variants in this gene. However, as other manifestations such as skeletal malformations and skin abnormalities represent more prominent features of the disorder, it is less likely that cases would be tested under the Arthrogryposis panel. EBP is already Green on other relevant panels (Skeletal dysplasia v2.100, Palmoplantar keratodermas v1.7, etc).
Arthrogryposis v3.102 EBP Arina Puzriakova Gene: ebp has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.122 FOXG1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FOXG1.
Dystonia, chorea or related movement disorder, childhood onset v1.122 FOXG1 Sarah Leigh edited their review of gene: FOXG1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. All of the patients with FOXG1 variants reported in PMID 27029630 abnormal involuntary movements, including chorea/athetosis in 22/25 (88%) cases.; Changed rating: GREEN
Dystonia, chorea or related movement disorder, childhood onset v1.122 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to 27029630
White matter disorders and cerebral calcification - childhood onset v1.143 RPIA Arina Puzriakova Publications for gene: RPIA were set to 31247379; 14988808; 31056085
Dystonia, chorea or related movement disorder, childhood onset v1.121 FOXG1 Sarah Leigh Classified gene: FOXG1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.121 FOXG1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.121 FOXG1 Sarah Leigh Gene: foxg1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.142 RPIA Arina Puzriakova Tag Q2_21_rating tag was added to gene: RPIA.
White matter disorders and cerebral calcification - childhood onset v1.142 RPIA Arina Puzriakova Classified gene: RPIA as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.142 RPIA Arina Puzriakova Added comment: Comment on list classification: Cerebral white matter abnormalities identified in all cases to date (at least 4 unrelated families) - sufficient for RPIA to be rated Green on this panel
White matter disorders and cerebral calcification - childhood onset v1.142 RPIA Arina Puzriakova Gene: rpia has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.198 FOXG1 Sarah Leigh edited their review of gene: FOXG1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. PMID 27029630 reports 85% (23/27) of patients with FOXG1 variants have microcephaly, defined as greater than 2 SDs below the mean for age, acquired postnatally in most cases.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.368 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to PMID: 21441262
Intellectual disability v3.1108 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Fetal anomalies v1.674 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Intellectual disability v3.1107 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, 613454; CONGENITAL VARIANT OF RETT SYNDROME (RTTCV) to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Early onset or syndromic epilepsy v2.367 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant to Rett syndrome, congenital variantRett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Fetal anomalies v1.673 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from CONGENITAL VARIANT OF RETT SYNDROME to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Severe microcephaly v2.198 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, MIM# 613454 to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Dystonia, chorea or related movement disorder, childhood onset v1.120 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett Syndrome, congenital variant, 613454 to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Severe microcephaly v2.197 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037
Severe microcephaly v2.196 FOXG1 Sarah Leigh Classified gene: FOXG1 as Amber List (moderate evidence)
Severe microcephaly v2.196 FOXG1 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 v2.196 FOXG1 Sarah Leigh Gene: foxg1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.195 FOXG1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FOXG1.
Dystonia, chorea or related movement disorder, childhood onset v1.119 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Clefting v2.32 RERE Catherine Snow Classified gene: RERE as Amber List (moderate evidence)
Clefting v2.32 RERE Catherine Snow Gene: rere has been classified as Amber List (Moderate Evidence).
Clefting v2.31 RERE Catherine Snow gene: RERE was added
gene: RERE was added to Clefting. Sources: Literature
Mode of inheritance for gene: RERE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RERE were set to PMID: 33772547
Phenotypes for gene: RERE were set to clefting
Review for gene: RERE was set to AMBER
Added comment: Expansion of phenotype. RERE associated with neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH)
A pathogenic, de novo c.4313_4318dupTCCACC proband had cleft palate, incomplete penetrance as other individuals with NEDBEH and same variant (PMID: 27087320 PMID: 29330883) did not display clefting phenotype. There is functional support in mouse models as RERE-deficient embryos have cleft palate. Previously one patient (subject 7) with NEDBEH has been described to have a cleft lip (PMID: 27087320) Therefore rating as Amber
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.141 BOLA3 Ivone Leong Tag Q2_21_rating tag was added to gene: BOLA3.
White matter disorders and cerebral calcification - childhood onset v1.141 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549; 29501406; 24334290; 21944046; 30302924; 29654549
Inherited white matter disorders v1.111 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549; 29501406; 24334290; 21944046; 30302924; 29654549
Inherited white matter disorders v1.110 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549, 29501406, 24334290, 21944046
Inherited white matter disorders v1.109 BOLA3 Ivone Leong Phenotypes for gene: BOLA3 were changed from to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, OMIM:614299
Inherited white matter disorders v1.108 BOLA3 Ivone Leong Classified gene: BOLA3 as Green List (high evidence)
Inherited white matter disorders v1.108 BOLA3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association.
Inherited white matter disorders v1.108 BOLA3 Ivone Leong Gene: bola3 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.140 BOLA3 Ivone Leong Classified gene: BOLA3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.140 BOLA3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.140 BOLA3 Ivone Leong Gene: bola3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.672 ZNF3 Arina Puzriakova gene: ZNF3 was added
gene: ZNF3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ZNF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF3 were set to 32732226
Phenotypes for gene: ZNF3 were set to Hydrocephaly; Facial cleft
Review for gene: ZNF3 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrocephaly and facial cleft detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including a median cleft palate, partial maxillar agenesis, bilateral severe microphthalmia, arhinencephaly, partial thalamic fusion. A homozygous truncating variant (c.396A>G/ p.*132Trpext*69) in ZNF3 was found by exome sequencing.
Sources: Literature
Fetal anomalies v1.671 WDR91 Arina Puzriakova gene: WDR91 was added
gene: WDR91 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226
Phenotypes for gene: WDR91 were set to Hygroma; Hydrocephaly
Review for gene: WDR91 was set to RED
Added comment: Novel candidate gene identified in a fetus with hygroma and hydrocephaly detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma, macrocephaly, abnormal ears, unilateral simian crease, hydrocephaly, cerebellar hypoplasia, and interventricular communication. A homozygous truncating variant was found by exome sequencing with concordant segregation among 4 affected fetus, 2 healthy sibs and both parents
Sources: Literature
Structural eye disease v1.69 WRAP73 Catherine Snow changed review comment from: Four individuals in two unrelated Indian families homozygous for missense variant c.1148C > T (p.Pro383Leu) in WRAP73 (old gene symbol WDR8) and reported to have Microspherophakia. Functional studies in Zebrafish showed knockout mutants and knockdown morphants exhibit decreased eye size. Amber rating as although functional evidence as new gene disease association with one missense.
Sources: Literature; to: Four individuals in two unrelated Indian families homozygous for missense variant c.1148C > T (p.Pro383Leu) in WRAP73 (old gene symbol WDR8) and reported to have Microspherophakia. Functional studies in Zebrafish showed knockout mutants and knockdown morphants exhibit decreased eye size. Amber rating as although functional evidence this is a new gene disease association with just one missense variant.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.139 BOLA3 Ivone Leong Phenotypes for gene: BOLA3 were changed from to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, OMIM:614299
White matter disorders and cerebral calcification - childhood onset v1.138 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549, 29501406, 24334290, 21944046
Structural eye disease v1.69 WRAP73 Catherine Snow Classified gene: WRAP73 as Amber List (moderate evidence)
Structural eye disease v1.69 WRAP73 Catherine Snow Gene: wrap73 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.670 SPTBN5 Arina Puzriakova gene: SPTBN5 was added
gene: SPTBN5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN5 were set to 32732226
Phenotypes for gene: SPTBN5 were set to Multicystic kidney; Oligohydramnios
Review for gene: SPTBN5 was set to RED
Added comment: Novel candidate gene identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis. Compound heterozygous variants including a truncating variant were found by exome sequencing.
Sources: Literature
Structural eye disease v1.68 WRAP73 Catherine Snow gene: WRAP73 was added
gene: WRAP73 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: WRAP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WRAP73 were set to PMID: 33693649
Phenotypes for gene: WRAP73 were set to Microspherophakia
Review for gene: WRAP73 was set to AMBER
Added comment: Four individuals in two unrelated Indian families homozygous for missense variant c.1148C > T (p.Pro383Leu) in WRAP73 (old gene symbol WDR8) and reported to have Microspherophakia. Functional studies in Zebrafish showed knockout mutants and knockdown morphants exhibit decreased eye size. Amber rating as although functional evidence as new gene disease association with one missense.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.137 AIFM1 Ivone Leong Tag Q2_21_rating tag was added to gene: AIFM1.
White matter disorders and cerebral calcification - childhood onset v1.137 AIFM1 Ivone Leong Classified gene: AIFM1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.137 AIFM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.137 AIFM1 Ivone Leong Gene: aifm1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.136 AIFM1 Ivone Leong Added comment: Comment on publications: PMID: 33439541 - 2 additional cases
White matter disorders and cerebral calcification - childhood onset v1.136 AIFM1 Ivone Leong Publications for gene: AIFM1 were set to 28842795; 27102849
Fetal anomalies v1.669 SCN7A Arina Puzriakova gene: SCN7A was added
gene: SCN7A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCN7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN7A were set to 32732226
Phenotypes for gene: SCN7A were set to Holoprosencephaly
Review for gene: SCN7A was set to RED
Added comment: Novel candidate gene identified in a fetus with holoprosencephaly detected by ultrasound. Autopsy showed multiple congenital abnormalities including IUGR, microcephaly, bilateral, ablepharon, corpus callosum agenesis, myelomeningocele, tracheal atresia, absent nipples, unilateral simian crease, and hypoplastic phalanges. Compound heterozygous variants including a truncating variant were found by exome sequencing with concordant segregation.
Sources: Literature
Fetal anomalies v1.668 MYBPC2 Arina Puzriakova gene: MYBPC2 was added
gene: MYBPC2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MYBPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBPC2 were set to 32732226
Phenotypes for gene: MYBPC2 were set to Fetal akinesia; Hydrops; Hygroma; Multiple pterygium
Review for gene: MYBPC2 was set to RED
Added comment: Novel candidate gene identified in a fetus with fetal akinesia detected by ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, hygroma, multiple pterygium. A homozygous variant (c.3394G>A/ p.Glu1132Lys) in MYBPC2 was found by exome sequencing with concordant segregation among one affected sib and two unaffected sibs.
Sources: Literature
Fetal anomalies v1.667 DNAH2 Arina Puzriakova changed review comment from: Novel candidate gene identified in a fetus with hydrops and complex cardiopathy detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex cardiopathy, hypotrophic splenium, and common mesentery. Compound heterozygous variants including a truncating variant were found exome sequencing.
Sources: Literature; to: Novel candidate gene identified in a fetus with hydrops and complex cardiopathy detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex cardiopathy, hypotrophic splenium, and common mesentery. Compound heterozygous variants including a truncating variant were found by exome sequencing.
Sources: Literature
Fetal anomalies v1.667 DNAH2 Arina Puzriakova gene: DNAH2 was added
gene: DNAH2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DNAH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH2 were set to 32732226
Phenotypes for gene: DNAH2 were set to Hydrops; Complex cardiopathy
Review for gene: DNAH2 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrops and complex cardiopathy detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex cardiopathy, hypotrophic splenium, and common mesentery. Compound heterozygous variants including a truncating variant were found exome sequencing.
Sources: Literature
Intellectual disability v3.1106 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from COFFIN SIRIS to Coffin-Siris syndrome 5, OMIM:616938
White matter disorders and cerebral calcification - childhood onset v1.135 AIFM1 Ivone Leong Phenotypes for gene: AIFM1 were changed from Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, MIM# 300232 to Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, OMIM:300232
White matter disorders and cerebral calcification - childhood onset v1.134 CNP Ivone Leong Tag watchlist tag was added to gene: CNP.
White matter disorders and cerebral calcification - childhood onset v1.134 CNP Ivone Leong Classified gene: CNP as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.134 CNP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
White matter disorders and cerebral calcification - childhood onset v1.134 CNP Ivone Leong Gene: cnp has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.133 CNP Ivone Leong Phenotypes for gene: CNP were changed from Hypomyelinating leukodystrophy to ?Leukodystrophy, hypomyelinating, 20, OMIM:619071
White matter disorders and cerebral calcification - childhood onset v1.132 GTF2H5 Ivone Leong edited their review of gene: GTF2H5: Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Based on the available evidence there is not enough evidence to support a gene-disease association. This gene should be demoted to Amber/Red at the next review.; Changed rating: AMBER
White matter disorders and cerebral calcification - childhood onset v1.132 GTF2H5 Ivone Leong Tag Q2_21_expert_review tag was added to gene: GTF2H5.
White matter disorders and cerebral calcification - childhood onset v1.132 GTF2H5 Ivone Leong Tag Q2_21_rating tag was added to gene: GTF2H5.
White matter disorders and cerebral calcification - childhood onset v1.132 GTF2H5 Ivone Leong Added comment: Comment on publications: 5 unrelated cases of patients with variants in this gene. There was no mention of any white matter changes in patients described in PMID: 24986372 and 15220921. PMID: 30359777, the affected patient had delayed myelination.
White matter disorders and cerebral calcification - childhood onset v1.132 GTF2H5 Ivone Leong Publications for gene: GTF2H5 were set to 24986372
White matter disorders and cerebral calcification - childhood onset v1.131 GTF2H5 Ivone Leong Phenotypes for gene: GTF2H5 were changed from Photosensitive trichothiodystrophy 3; Trichothiodystrophy 3, photosensitive to delayed myelination
Fetal anomalies v1.666 SMARCC1 Arina Puzriakova Penetrance for gene SMARCC1 was set from to None
Hydrocephalus v2.105 SMARCC1 Arina Puzriakova Penetrance for gene SMARCC1 was set from to None
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.; to: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update - sufficient cases (>3) of congenital hydrocephaly which may conceivably be detected prenatally.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova Entity copied from Hydrocephalus v2.104
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova gene: SMARCC1 was added
gene: SMARCC1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: SMARCC1.
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCC1 were set to 24170322; 29983323; 32732226; 33077954
Phenotypes for gene: SMARCC1 were set to Congenital hydrocephalus; Aqueductal stenosis; Septal agenesis; Corpus callosum abnormalities
Hydrocephalus v2.104 SMARCC1 Arina Puzriakova Phenotypes for gene: SMARCC1 were changed from Congenital hydrocephalus to Congenital hydrocephalus; Aqueductal stenosis; Septal agenesis; Corpus callosum abnormalities
Hydrocephalus v2.103 SMARCC1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SMARCC1.
Hydrocephalus v2.103 SMARCC1 Arina Puzriakova Publications for gene: SMARCC1 were set to 33077954; 24170322
Hydrocephalus v2.102 SMARCC1 Arina Puzriakova Classified gene: SMARCC1 as Amber List (moderate evidence)
Hydrocephalus v2.102 SMARCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.
Hydrocephalus v2.102 SMARCC1 Arina Puzriakova Gene: smarcc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1105 SMARCC1 Arina Puzriakova Mode of inheritance for gene: SMARCC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1104 DPH1 Arina Puzriakova Publications for gene: DPH1 were set to 29362492; 29410513; 26220823; 25558065
Intellectual disability v3.1103 DPH1 Arina Puzriakova Phenotypes for gene: DPH1 were changed from Developmental delay with short stature, dysmorphic features, and sparse hair, 616901 to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Fetal anomalies v1.664 DPH1 Arina Puzriakova Classified gene: DPH1 as Amber List (moderate evidence)
Fetal anomalies v1.664 DPH1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of fetally-relevant phenotypes from unrelated families to warrant a Green rating on this panel.
Fetal anomalies v1.664 DPH1 Arina Puzriakova Gene: dph1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.663 DPH1 Arina Puzriakova gene: DPH1 was added
gene: DPH1 was added to Fetal anomalies. Sources: Literature
Q2_21_rating tags were added to gene: DPH1.
Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH1 were set to 25558065; 29362492; 30877278; 32732226
Phenotypes for gene: DPH1 were set to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Review for gene: DPH1 was set to GREEN
Added comment: Biallelic variants in this gene cause a neurodevelopmental disorder characterised by ID/DD, short stature, dysmorphic features, craniofacial and ectodermal anomalies. Several reports note antenatal anomalies and multiple congenital abnormalities that may conceivably be detected prenatally.

Fetal ultrasound phenotypes reported in literature include IUGR, polyhydramnios, craniostenosis, cardiac abnormalities, brain anomalies, and polydactyly (PMID: 25558065; 29362492; 30877278; 32732226)
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.130 GTF2H5 Ivone Leong Publications for gene: GTF2H5 were set to
Severe microcephaly v2.195 MCM7 Arina Puzriakova Classified gene: MCM7 as Amber List (moderate evidence)
Severe microcephaly v2.195 MCM7 Arina Puzriakova Added comment: Comment on list classification: Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (PMIDs: 33654309; 34059554). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.

As no clear phenotype correlations can be made at this time, rating as Amber in anticipation of further cases (2/3 presented severe microcephaly).
Severe microcephaly v2.195 MCM7 Arina Puzriakova Gene: mcm7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.194 MCM7 Arina Puzriakova gene: MCM7 was added
gene: MCM7 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability
Review for gene: MCM7 was set to AMBER
Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. Currently, MCM7 is not associated with any phenotype in OMIM or G2P.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.129 ISCA1 Ivone Leong Tag Q2_21_rating tag was added to gene: ISCA1.
White matter disorders and cerebral calcification - childhood onset v1.129 ISCA1 Ivone Leong Classified gene: ISCA1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.129 ISCA1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.129 ISCA1 Ivone Leong Gene: isca1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.128 ISCA1 Ivone Leong Phenotypes for gene: ISCA1 were changed from Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613 to Multiple mitochondrial dysfunctions syndrome 5, OMIM:617613
Intellectual disability v3.1102 SLC6A1 Arina Puzriakova Publications for gene: SLC6A1 were set to 25865495
Early onset or syndromic epilepsy v2.366 SLC6A1 Arina Puzriakova Publications for gene: SLC6A1 were set to 25865495; Carvill et al (2015) Am J Hum Genet 96(5): 808-15
Intellectual disability v3.1101 SLC6A1 Arina Puzriakova Phenotypes for gene: SLC6A1 were changed from EPILEPSY WITH MYOCLONIC-ATONIC SEIZURES to Myoclonic-atonic epilepsy, OMIM:616421
Early onset or syndromic epilepsy v2.365 SLC6A1 Arina Puzriakova Phenotypes for gene: SLC6A1 were changed from Myoclonic-atonic epilepsy, 616421 to Myoclonic-atonic epilepsy, OMIM:616421
Intellectual disability v3.1100 SMARCA5 Julia Baptista gene: SMARCA5 was added
gene: SMARCA5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to intellectual disability; postnatal microcephaly; hypotonia; failure to thrive
Penetrance for gene: SMARCA5 were set to unknown
Review for gene: SMARCA5 was set to GREEN
Added comment: The authors identified seven missense variants, one splice-altering variant that led to exon skipping and in-frame deletion, and one recurrent in-frame deletion in 12 individuals from
10 unrelated families. The variant was de novo in nine individuals. They presented a broad range of clinical features from isolated autism to syndromic intellectual disability.
Sources: Literature
Limb disorders v2.42 GLI3 Arina Puzriakova Publications for gene: GLI3 were set to 31115189
Skeletal dysplasia v2.100 GLI3 Arina Puzriakova Publications for gene: GLI3 were set to
Limb disorders v2.41 GLI3 Arina Puzriakova reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32591344; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.99 GLI3 Arina Puzriakova reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32591344; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia, adult onset v2.71 AMPD2 Zornitza Stark edited their review of gene: AMPD2: Changed rating: RED
Hereditary ataxia, adult onset v2.71 VPS41 James Polke gene: VPS41 was added
gene: VPS41 was added to Hereditary ataxia - adult onset. Sources: NHS GMS
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32367058; 33875678
Phenotypes for gene: VPS41 were set to Generalised Neurodevelopmental disorder; Ataxia; Dystonia
Review for gene: VPS41 was set to GREEN
Added comment: 32808683: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.

PMID 33764426: Additional 9 individuals from 5 unrelated families reported.
Sources: NHS GMS
Ataxia and cerebellar anomalies - childhood onset v2.190 VPS41 James Polke gene: VPS41 was added
gene: VPS41 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: NHS GMS
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426
Phenotypes for gene: VPS41 were set to Generalised Neurodevelopmental disorder; Ataxia; Dystonia
Review for gene: VPS41 was set to GREEN
Added comment: 32808683: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.

PMID 33764426: Additional 9 individuals from 5 unrelated families reported.
Sources: NHS GMS
Dystonia, chorea or related movement disorder, adult onset v1.114 VPS41 James Polke gene: VPS41 was added
gene: VPS41 was added to Adult onset movement disorder. Sources: NHS GMS
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426
Phenotypes for gene: VPS41 were set to Generalised Neurodevelopmental disorder; Ataxia; Dystonia
Review for gene: VPS41 was set to GREEN
Added comment: 32808683: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.

PMID 33764426: Additional 9 individuals from 5 unrelated families reported.
Sources: NHS GMS
Dystonia, chorea or related movement disorder, adult onset v1.114 VPS16 James Polke gene: VPS16 was added
gene: VPS16 was added to Adult onset movement disorder. Sources: NHS GMS
Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS16 were set to 32808683
Phenotypes for gene: VPS16 were set to Dystonia; Dystonia Associated with Lysosomal Abnormalities; Dystonia 30; OMIM #619291
Review for gene: VPS16 was set to GREEN
Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood.

Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: NHS GMS
Hereditary spastic paraplegia, adult onset v1.23 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.23 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as green, but with a recommendation for review of this gene at the next GMS review as all cases have onset in childhood and this is an adult onset panel.
Hereditary spastic paraplegia, adult onset v1.23 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Green List (High Evidence).
Hereditary spastic paraplegia, adult onset v1.22 SLC1A4 Eleanor Williams Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657
Hereditary spastic paraplegia, adult onset v1.21 SLC1A4 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SLC1A4.
Tag Q2_21_phenotype tag was added to gene: SLC1A4.
Hereditary neuropathy or pain disorder v1.25 SORD James Polke reviewed gene: SORD: Rating: GREEN; Mode of pathogenicity: None; Publications: 32367058, 33875678; Phenotypes: Peripheral Neuropathy, Charcot-Marie Tooth Disease, Sorbitol dehydrogenase deficiency with peripheral neuropathy (OMIM # 618912); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.174 SORL1 James Polke gene: SORL1 was added
gene: SORL1 was added to Neurodegenerative disorders - adult onset. Sources: NHS GMS
Mode of inheritance for gene: SORL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SORL1 were set to 28537274; 22472873; 28595629; 32587946
Phenotypes for gene: SORL1 were set to Alzheimer's Disease
Penetrance for gene: SORL1 were set to unknown
Review for gene: SORL1 was set to AMBER
Added comment: Proposed as an amber gene. A published risk locus for late onset Alzheimer's. Some case studies propose a cause of familial early onset AD, though insufficient cases/segregation at present.
Sources: NHS GMS
Severe microcephaly v2.193 TPRKB Eleanor Williams Phenotypes for gene: TPRKB were changed from Galloway-Mowat syndrome 5, MIM# 617731 to Galloway-Mowat syndrome 5, OMIM:617731
Severe microcephaly v2.192 TPRKB Eleanor Williams Publications for gene: TPRKB were set to 28805828; 30053862
Severe microcephaly v2.191 TPRKB Eleanor Williams Classified gene: TPRKB as Red List (low evidence)
Severe microcephaly v2.191 TPRKB Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. 2 unrelated cases reported but the degree of microcephaly is not reported, so can't confirm it is in the severe range.
Severe microcephaly v2.191 TPRKB Eleanor Williams Gene: tprkb has been classified as Red List (Low Evidence).
Severe microcephaly v2.190 TPRKB Eleanor Williams reviewed gene: TPRKB: Rating: RED; Mode of pathogenicity: None; Publications: 28805828; Phenotypes: Galloway-Mowat syndrome 5, OMIM:617731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.190 SLC1A4 Eleanor Williams Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657
Severe microcephaly v2.189 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890 to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, OMIM:618890
Glaucoma (developmental) v1.36 PAX6 Eleanor Williams Mode of inheritance for gene: PAX6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited white matter disorders v1.107 HSPD1 Ivone Leong Classified gene: HSPD1 as Green List (high evidence)
Inherited white matter disorders v1.107 HSPD1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. The missense p.Leu47Val variant has a dominant negative effect.

This gene is also Amber with a recommendation to promote to Green on the White matter disorders and cerebral calcification - narrow panel (Version 1.127). With the following review from Zornitza Stark (Australian Genomics):

"Multiple families reported with bi-allelic variants in HSPD1 and hypomyelinating leukodystrophy. Supportive mouse model. In addition, two unrelated individuals reported with same de novo missense p.Leu47Val and leukodystrophy.
Zornitza Stark (Australian Genomics), 15 Sep 2020"
Inherited white matter disorders v1.107 HSPD1 Ivone Leong Gene: hspd1 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.106 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to 18571143; 28377887
White matter disorders and cerebral calcification - childhood onset v1.127 HSPD1 Ivone Leong Classified gene: HSPD1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.127 HSPD1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

The missense p.Leu47Val variant has a dominant negative effect.
White matter disorders and cerebral calcification - childhood onset v1.127 HSPD1 Ivone Leong Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.39 HIKESHI Ivone Leong Tag Q2_21_rating tag was added to gene: HIKESHI.
White matter disorders and cerebral calcification - childhood onset v1.126 HIKESHI Ivone Leong Tag Q2_21_rating tag was added to gene: HIKESHI.
White matter disorders and cerebral calcification - childhood onset v1.126 HSPD1 Ivone Leong Tag Q2_21_rating tag was added to gene: HSPD1.
Inherited white matter disorders v1.105 HSPD1 Ivone Leong Mode of inheritance for gene: HSPD1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.126 HSPD1 Ivone Leong Mode of inheritance for gene: HSPD1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.364 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1100 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
White matter disorders and cerebral calcification - childhood onset v1.125 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to 18571143; 27405012; 32532876; 28377887; 27405012
Inherited white matter disorders v1.104 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280; Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Inherited white matter disorders v1.103 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to
White matter disorders and cerebral calcification - childhood onset v1.124 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, OMIM:612233; Spastic paraplegia 13, autosomal dominant, OMIM:605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Severe microcephaly v2.188 TP53RK Eleanor Williams Phenotypes for gene: TP53RK were changed from Galloway-Mowat syndrome 4, MIM# 617730 to Galloway-Mowat syndrome 4, OMIM:617730
Severe microcephaly v2.187 TP53RK Eleanor Williams reviewed gene: TP53RK: Rating: RED; Mode of pathogenicity: None; Publications: 28805828, 30053862; Phenotypes: Galloway-Mowat syndrome 4, OMIM:17730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.187 TCF4 Eleanor Williams Phenotypes for gene: TCF4 were changed from Pitt-Hopkins syndrome, MIM# 610954 to Pitt-Hopkins syndrome, OMIM:610954
Severe microcephaly v2.186 TCF4 Eleanor Williams Publications for gene: TCF4 were set to 18728071; 22934316
Severe microcephaly v2.185 TCF4 Eleanor Williams reviewed gene: TCF4: Rating: AMBER; Mode of pathogenicity: None; Publications: 18728071, 21671391, 29318938; Phenotypes: Pitt-Hopkins syndrome OMIM:610954; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ichthyosis and erythrokeratoderma v1.60 ASPRV1 Catherine Snow Tag Q2_21_rating tag was added to gene: ASPRV1.
Ichthyosis and erythrokeratoderma v1.60 ASPRV1 Catherine Snow reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32516568; Phenotypes: Ichthyosis, lamellar, autosomal dominant, OMIM #146750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v1.60 TRPV3 Catherine Snow Tag Q2_21_NHS_review was removed from gene: TRPV3.
Ichthyosis and erythrokeratoderma v1.60 TRPV3 Catherine Snow Tag Q2_21_rating tag was added to gene: TRPV3.
Tag Q2_21_NHS_review tag was added to gene: TRPV3.
Ichthyosis and erythrokeratoderma v1.60 TRPV3 Catherine Snow reviewed gene: TRPV3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.21 SLC1A4 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: SLC1A4.
Hereditary spastic paraplegia, adult onset v1.21 SLC1A4 Eleanor Williams commented on gene: SLC1A4
White matter disorders and cerebral calcification - childhood onset v1.123 POLH Arina Puzriakova changed review comment from: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update. Literature search did not revealed any evidence of involvement in white matter disease or intracranial calcification.; to: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update. Literature search did not reveal any evidence of involvement in white matter disease or intracranial calcification.
White matter disorders and cerebral calcification - childhood onset v1.123 POLH Arina Puzriakova Tag Q2_21_rating tag was added to gene: POLH.
White matter disorders and cerebral calcification - childhood onset v1.123 POLH Arina Puzriakova Classified gene: POLH as Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.123 POLH Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update. Literature search did not revealed any evidence of involvement in white matter disease or intracranial calcification.
White matter disorders and cerebral calcification - childhood onset v1.123 POLH Arina Puzriakova Gene: polh has been classified as Green List (High Evidence).
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Amber List (moderate evidence)
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation for Green review, following confirmation that progressive microcephaly is within the scope of this panel. 4 different variants reported.
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.184 SLC1A4 Eleanor Williams Tag founder-effect tag was added to gene: SLC1A4.
Tag Q2_21_rating tag was added to gene: SLC1A4.
Severe microcephaly v2.184 SLC1A4 Eleanor Williams reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25930971, 26138499, 26041762, 27193218, 29989513; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly OMIM:616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.102 RAB11B Arina Puzriakova Classified gene: RAB11B as Green List (high evidence)
Inherited white matter disorders v1.102 RAB11B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green. At least 2 variants reported in 5 unrelated cases, of which white matter abnormalities were reported in all cases (4) for which brain imaging was available.
Inherited white matter disorders v1.102 RAB11B Arina Puzriakova Gene: rab11b has been classified as Green List (High Evidence).
Inherited white matter disorders v1.101 RAB11B Arina Puzriakova reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - childhood onset v1.122 RAB11B Arina Puzriakova Classified gene: RAB11B as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.122 RAB11B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update
White matter disorders and cerebral calcification - childhood onset v1.122 RAB11B Arina Puzriakova Gene: rab11b has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.121 RAB11B Arina Puzriakova Tag Q2_21_rating tag was added to gene: RAB11B.
White matter disorders and cerebral calcification - childhood onset v1.121 RAB11B Arina Puzriakova reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - childhood onset v1.121 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to
White matter disorders and cerebral calcification - childhood onset v1.120 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, 612233; Spastic paraplegia 13, autosomal dominant, 605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233; Spastic paraplegia 13, autosomal dominant, OMIM:605280
Hereditary spastic paraplegia v1.224 HIKESHI Ivone Leong Classified gene: HIKESHI as Green List (high evidence)
Hereditary spastic paraplegia v1.224 HIKESHI Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on my previous review.
Hereditary spastic paraplegia v1.224 HIKESHI Ivone Leong Gene: hikeshi has been classified as Green List (High Evidence).
Severe microcephaly v2.184 HIKESHI Ivone Leong Classified gene: HIKESHI as Red List (low evidence)
Severe microcephaly v2.184 HIKESHI Ivone Leong Added comment: Comment on list classification: Downgraded from Amber to Red as microcephaly is not severe enough in the patients and also only seen in Ashkenazi Jewish families.
Severe microcephaly v2.184 HIKESHI Ivone Leong Gene: hikeshi has been classified as Red List (Low Evidence).
Optic neuropathy v2.41 HIKESHI Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association (only 2 cases with optic atrophy), therefore this gene has been given an Amber rating.
Optic neuropathy v2.41 HIKESHI Ivone Leong Tag watchlist tag was added to gene: HIKESHI.
Optic neuropathy v2.41 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Optic neuropathy v2.41 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Optic neuropathy. Sources: Expert list,Expert Review Amber
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Severe microcephaly v2.183 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Severe microcephaly v2.183 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Severe microcephaly. Sources: Expert list,Expert Review Amber
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Hereditary spastic paraplegia v1.223 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Hereditary spastic paraplegia v1.223 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Hereditary spastic paraplegia, childhood onset v2.39 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Hereditary spastic paraplegia, childhood onset v2.39 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
White matter disorders and cerebral calcification - childhood onset v1.119 HIKESHI Ivone Leong Classified gene: HIKESHI as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.119 HIKESHI Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.119 HIKESHI Ivone Leong Gene: hikeshi has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.118 HIKESHI Ivone Leong Tag watchlist was removed from gene: HIKESHI.
White matter disorders and cerebral calcification - childhood onset v1.118 HIKESHI Ivone Leong Tag watchlist tag was added to gene: HIKESHI.
White matter disorders and cerebral calcification - childhood onset v1.118 HIKESHI Ivone Leong Added comment: Comment on publications: PMID: 26545878. 3 unrelated cases (6 individuals), Ashkenazi Jewish families. p.Val54Leu. 4/4 (2 MRI was not reported) delayed myelination and periventricular white matter abnormalities on brain imaging, 5/6 feeding difficulties, 5/6 developmental delay, 5/5 progressively decreasing head circumference percentile (up to -2 SD), 6/6 spasticity, 5/6 increased muscle tone, 1/6 ataxia, 2/6 (same family) optic atrophy, 4/6 nystagmus, 1/6 heart failure, 1/6 perimyocarditis.

PMID: 28000699. Finnish case. Difference variant than what was described in PMID:26545878 (p.Cys4Ser). Diffuse hypomyelination, cystic changes of periventricular white matter, has increased muscle tone, spasticity, ataxia, mild optic atrophy, myopia nystagmus and epilepsy. No feeding difficulties or microcephaly.
White matter disorders and cerebral calcification - childhood onset v1.118 HIKESHI Ivone Leong Publications for gene: HIKESHI were set to 26545878
White matter disorders and cerebral calcification - childhood onset v1.117 NFU1 Arina Puzriakova edited their review of gene: NFU1: Changed publications to: 22077971, 25918518, 28470589, 29441221, 31516295, 32747156, 32669393
White matter disorders and cerebral calcification - childhood onset v1.117 NFU1 Arina Puzriakova Publications for gene: NFU1 were set to 22077971; 28470589; 29441221; 31516295; 32747156; 32669393
Pulmonary arterial hypertension v2.15 NFU1 Arina Puzriakova Classified gene: NFU1 as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.15 NFU1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene as Green at the next GMS panel update - sufficient number of unrelated cases (>3) supported by a NFU1 deficiency rat model which exhibited PAH.
Pulmonary arterial hypertension v2.15 NFU1 Arina Puzriakova Gene: nfu1 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.14 NFU1 Arina Puzriakova gene: NFU1 was added
gene: NFU1 was added to Pulmonary arterial hypertension. Sources: Literature
Q2_21_rating tags were added to gene: NFU1.
Mode of inheritance for gene: NFU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFU1 were set to 22077971; 25918518; 28470589; 31516295; 32669393; 31461310
Phenotypes for gene: NFU1 were set to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Pulmonary hypertension in early infancy
Review for gene: NFU1 was set to GREEN
Added comment: Biallelic variants in this gene cause multiple mitochondrial dysfunctions syndrome, a severe neonatal onset disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, leukodystrophy, lactic acidosis, and early death.

More than 50% of infant patients are found to display significant PAH, which can initially be an isolated and prominent finding (PMID: 22077971; 25918518; 28470589; 31516295; 32669393). Pulmonary samples from NFU1-deficient individuals with PAH showed obstructive vasculopathy with proximal and acinar arterial involvement (PMID: 22077971).

Humanised rare model of NFU1 deficiency showed features of mitochondrial dysfunction comparable to those observed in patients and also developed PAH (PMID: 31461310)
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.116 NFU1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NFU1.
White matter disorders and cerebral calcification - childhood onset v1.116 NFU1 Arina Puzriakova Publications for gene: NFU1 were set to 21944046; 22077971; 32747156; 29441221
White matter disorders and cerebral calcification - childhood onset v1.115 NFU1 Arina Puzriakova Classified gene: NFU1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.115 NFU1 Arina Puzriakova Added comment: Comment on list classification: Overall there are sufficient unrelated cases (>3) with white matter abnormalities to rate this gene as Green on this panel.
White matter disorders and cerebral calcification - childhood onset v1.115 NFU1 Arina Puzriakova Gene: nfu1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.114 NFU1 Arina Puzriakova reviewed gene: NFU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22077971, 28470589, 29441221, 31516295, 32747156, 32669393; Phenotypes: Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711, Leukoencephalopathy, HP:0002352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.114 HIKESHI Ivone Leong Phenotypes for gene: HIKESHI were changed from Leukodystrophy, hypomyelinating, 13, MIM# 616881 to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Intellectual disability v3.1100 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency, 608611; Ribose 5-phosphate isomerase deficiency, MIM 608611. to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Likely inborn error of metabolism v2.139 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); Ribose 5-phosphate isomerase deficiency, OMIM:608611
Early onset or syndromic epilepsy v2.364 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Undiagnosed metabolic disorders v1.459 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); Ribose 5-phosphate isomerase deficiency, OMIM:608611
White matter disorders and cerebral calcification - childhood onset v1.113 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from Ribose 5-phosphate isomerase deficiency, MIM# 608611 to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Intellectual disability v3.1099 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, 617807; Intellectual disability to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Early onset or syndromic epilepsy v2.363 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, 617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Inherited white matter disorders v1.101 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, MIM#617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
White matter disorders and cerebral calcification - childhood onset v1.112 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, MIM#617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
White matter disorders and cerebral calcification - childhood onset v1.111 PTEN Arina Puzriakova Phenotypes for gene: PTEN were changed from Cowden syndrome 1, MIM# 158350 to Cowden syndrome 1, OMIM:158350
Hereditary ataxia, adult onset v2.71 TBC1D23 Sarah Leigh commented on gene: TBC1D23
Hereditary ataxia, adult onset v2.71 TBC1D23 Sarah Leigh Phenotypes for gene: TBC1D23 were changed from Pontocerebellar hypoplasia type 11, 617695 to Pontocerebellar hypoplasia type 11 OMIM:617695; pontocerebellar hypoplasia, type 11 MONDO:0054669
Hereditary ataxia, adult onset v2.70 TBC1D23 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: TBC1D23.
Ataxia and cerebellar anomalies - childhood onset v2.190 SLC9A1 Sarah Leigh Tag Q2_21_rating tag was added to gene: SLC9A1.
Structural eye disease v1.67 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from XERODERMA PIGMENTOSUM, VARIANT TYPE, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Adult solid tumours cancer susceptibility v2.10 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Childhood solid tumours v2.18 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.9 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Ataxia and cerebellar anomalies - childhood onset v2.190 SLC9A1 Sarah Leigh reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - childhood onset v1.110 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Mitochondrial disorders v2.39 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Likely inborn error of metabolism v2.138 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Possible mitochondrial disorder, nuclear genes v1.45 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1, 605711 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Undiagnosed metabolic disorders v1.458 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple mitochondrial dysfunctions syndrome 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Pyruvate dehydrogenase (PDH) deficiency v1.30 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1 OMIM:605711; multiple mitochondrial dysfunctions syndrome 1 MONDO:0011582 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Multiple mitochondrial dysfunctions syndrome 1, MONDO:0011582
Ataxia and cerebellar anomalies - childhood onset v2.190 SLC9A1 Sarah Leigh Classified gene: SLC9A1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.190 SLC9A1 Sarah Leigh Gene: slc9a1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.70 SLC9A1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: SLC9A1.
Hereditary ataxia, adult onset v2.70 SLC9A1 Sarah Leigh commented on gene: SLC9A1
Hereditary ataxia, adult onset v2.70 SLC9A1 Sarah Leigh Phenotypes for gene: SLC9A1 were changed from Lichtenstein-Knorr Syndrome to Lichtenstein-Knorr syndrome OMIM:616291; Lichtenstein-Knorr syndrome MONDO:0014572
Ataxia and cerebellar anomalies - childhood onset v2.189 SLC9A1 Sarah Leigh Phenotypes for gene: SLC9A1 were changed from Lichtenstein-Knorr syndrome, MIM# 616291 to Lichtenstein-Knorr syndrome OMIM:616291; Lichtenstein-Knorr syndrome MONDO:0014572
Hereditary ataxia, adult onset v2.69 SLC9A1 Sarah Leigh Publications for gene: SLC9A1 were set to
Intellectual disability v3.1098 SCYL1 Sarah Leigh Tag watchlist was removed from gene: SCYL1.
Tag Q2_21_rating tag was added to gene: SCYL1.
Intellectual disability v3.1098 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
White matter disorders and cerebral calcification - childhood onset v1.109 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Intellectual disability v3.1097 SCYL1 Sarah Leigh reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.188 NAXE Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Added to this panel as acute/early-onset ataxia is described in several cases as one of the first symptoms of disease and inclusion may allow for earlier detection. Other cerebellar signs such as nystagmus and dysarthria also reported.
Ataxia and cerebellar anomalies - childhood onset v2.188 NAXE Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.108
Ataxia and cerebellar anomalies - childhood onset v2.188 NAXE Arina Puzriakova gene: NAXE was added
gene: NAXE was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber
Q2_21_rating tags were added to gene: NAXE.
Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXE were set to 27616477; 27122014; 27290639; 30022751; 31758406; 31745726
Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Intellectual disability v3.1097 SCYL1 Sarah Leigh Publications for gene: SCYL1 were set to 26581903; 30914295
Inherited white matter disorders v1.100 NAXE Arina Puzriakova Classified gene: NAXE as Green List (high evidence)
Inherited white matter disorders v1.100 NAXE Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green. Sufficient number of unrelated cases (>3) with white matter abnormalities to rate as Green on this panel.
Inherited white matter disorders v1.100 NAXE Arina Puzriakova Gene: naxe has been classified as Green List (High Evidence).
Intellectual disability v3.1096 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Inherited white matter disorders v1.99 NAXE Arina Puzriakova Publications for gene: NAXE were set to 27616477, 27122014
Inherited white matter disorders v1.98 NAXE Arina Puzriakova reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27616477, 27122014, 27290639, 30022751, 31758406, 31745726; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, OMIM:617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.187 SCYL1 Sarah Leigh Tag Q2_21_rating tag was added to gene: SCYL1.
Ataxia and cerebellar anomalies - childhood onset v2.187 SCYL1 Sarah Leigh edited their review of gene: SCYL1: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least nine variants reported in at least seven cases.; Changed rating: GREEN
White matter disorders and cerebral calcification - childhood onset v1.108 NAXE Arina Puzriakova Publications for gene: NAXE were set to 27616477, 27122014
White matter disorders and cerebral calcification - childhood onset v1.107 NAXE Arina Puzriakova edited their review of gene: NAXE: Changed publications to: 27616477, 27122014, 27290639, 30022751, 31758406, 31745726; Changed phenotypes to: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, OMIM:617186
Ataxia and cerebellar anomalies - childhood onset v2.187 SCYL1 Sarah Leigh Classified gene: SCYL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.187 SCYL1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.187 SCYL1 Sarah Leigh Gene: scyl1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.107 NAXE Arina Puzriakova Classified gene: NAXE as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.107 NAXE Arina Puzriakova Gene: naxe has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.106 NAXE Arina Puzriakova Classified gene: NAXE as Red List (low evidence)
White matter disorders and cerebral calcification - childhood onset v1.106 NAXE Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
White matter disorders and cerebral calcification - childhood onset v1.106 NAXE Arina Puzriakova Gene: naxe has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.105 NAXE Arina Puzriakova Tag Q2_21_rating tag was added to gene: NAXE.
White matter disorders and cerebral calcification - childhood onset v1.105 NAXE Arina Puzriakova reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, OMIM:617186; Phenotypes: 27616477, 27122014, 27290639, 30022751, 31758406, 31745726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.68 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Ataxia and cerebellar anomalies - childhood onset v2.186 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Hereditary ataxia, adult onset v2.67 SCYL1 Sarah Leigh commented on gene: SCYL1
Hereditary ataxia, adult onset v2.67 SCYL1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: SCYL1.
Ataxia and cerebellar anomalies - childhood onset v2.185 RORA Sarah Leigh Tag Q2_21_rating tag was added to gene: RORA.
Ataxia and cerebellar anomalies - childhood onset v2.185 RORA Sarah Leigh edited their review of gene: RORA: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in at least four cases with ataxia (PMID 29656859).; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.185 RORA Sarah Leigh Classified gene: RORA as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.185 RORA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.185 RORA Sarah Leigh Gene: rora has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.67 RORA Sarah Leigh Publications for gene: RORA were set to
Hereditary ataxia, adult onset v2.66 RORA Sarah Leigh Tag Q2_21_phenotype tag was added to gene: RORA.
Hereditary ataxia, adult onset v2.66 RORA Sarah Leigh commented on gene: RORA
Hereditary ataxia, adult onset v2.66 RORA Sarah Leigh Phenotypes for gene: RORA were changed from Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, 618060 to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia OMIM:618060; intellectual developmental disorder with or without epilepsy or cerebellar ataxia MONDO:0060745
Ataxia and cerebellar anomalies - childhood onset v2.184 RORA Sarah Leigh Phenotypes for gene: RORA were changed from Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060 to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia OMIM:618060; intellectual developmental disorder with or without epilepsy or cerebellar ataxia MONDO:0060745
Hereditary ataxia, adult onset v2.65 AP1S2 Sarah Leigh Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340; Pettigrew syndrome to Mental retardation, X-linked syndromic 5 OMIM:304340; syndromic X-linked intellectual disability 5 MONDO:0010574
Intellectual disability v3.1095 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Epilepsy, progressive myoclonic 1B, 612437 to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Early onset or syndromic epilepsy v2.362 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Epilepsy, progressive myoclonic 1B 612437 to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Hereditary ataxia, adult onset v2.64 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B, 612437; Progressive Myoclonus Epilepsy with Ataxia to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Hereditary ataxia, adult onset v2.63 PRICKLE1 Sarah Leigh Publications for gene: PRICKLE1 were set to
Hereditary ataxia, adult onset v2.62 PRICKLE1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: PRICKLE1.
Hereditary ataxia, adult onset v2.62 PRICKLE1 Sarah Leigh commented on gene: PRICKLE1
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Mitochondrial disorders v2.38 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Possible mitochondrial disorder, nuclear genes v1.44 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Likely inborn error of metabolism v2.137 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Inherited white matter disorders v1.98 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, MIM#617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
White matter disorders and cerebral calcification - childhood onset v1.105 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, MIM#617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Hereditary ataxia, adult onset v2.62 AP1S2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AP1S2.
Hereditary ataxia, adult onset v2.62 AMPD2 Sarah Leigh Phenotypes for gene: AMPD2 were changed from Pontocerebellar hyoplasia 9, 615809 to Pontocerebellar hyoplasia 9 OMIM:615809; pontocerebellar hypoplasia type 9 MONDO:0014351
Hereditary ataxia, adult onset v2.61 AMPD2 Sarah Leigh Added comment: Comment on phenotypes: Spastic paraplegia 63 OMIM:615686 from homozygous frameshift reported in single family (Novarino et al, 2014).
Hereditary ataxia, adult onset v2.61 AMPD2 Sarah Leigh Phenotypes for gene: AMPD2 were changed from Pontocerebellar hyoplasia 9, 615809; Pontocerebellar hypoplasia 9 (#615809); Spastic paraplegia homozygous frameshift reported in single family (Novarino et al, 2014). to Pontocerebellar hyoplasia 9, 615809
Hereditary ataxia, adult onset v2.60 AMPD2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AMPD2.
Hereditary ataxia, adult onset v2.60 AMPD2 Sarah Leigh commented on gene: AMPD2
Hereditary ataxia, adult onset v2.60 ADGRG1 Sarah Leigh Phenotypes for gene: ADGRG1 were changed from Polymicrogyria, Frontoparietal, 606854; Polymicrogyria, perisylvian type, 615752 to Polymicrogyria, Frontoparietal OMIM:606854; bilateral frontoparietal polymicrogyria MONDO:0011738; Polymicrogyria, perisylvian type OMIM:615752; polymicrogyria, bilateral perisylvian, autosomal recessive MONDO:0014333
Hereditary ataxia, adult onset v2.59 ADGRG1 Sarah Leigh commented on gene: ADGRG1
Hereditary ataxia, adult onset v2.59 ADGRG1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ADGRG1.
Hereditary ataxia, adult onset v2.59 ABCB7 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ABCB7.
Hereditary ataxia, adult onset v2.59 ABCB7 Sarah Leigh commented on gene: ABCB7
Likely inborn error of metabolism v2.136 ABCB7 Sarah Leigh Added comment: Comment on phenotypes: Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only));congenital cerebellar hypoplasia/atrophy (PMID: 26242992).;Disorders of iron homeostasis
Likely inborn error of metabolism v2.136 ABCB7 Sarah Leigh Phenotypes for gene: ABCB7 were changed from Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); congenital cerebellar hypoplasia/atrophy (PMID: 26242992).; Anemia, sideroblastic, with ataxia; Disorders of iron homeostasis to Anemia, sideroblastic, with ataxia OMIM:301310; X-linked sideroblastic anemia with ataxia MONDO:0010524
Hereditary ataxia, adult onset v2.59 ABCB7 Sarah Leigh Phenotypes for gene: ABCB7 were changed from Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021 to Anemia, sideroblastic, with ataxia OMIM:301310; X-linked sideroblastic anemia with ataxia MONDO:0010524
Hereditary ataxia, adult onset v2.58 ABCB7 Sarah Leigh Phenotypes for gene: ABCB7 were changed from Anemia, sideroblastic, with ataxia; Anemia, sideroblast with ataxia, 300135; Sideroblastic Anemia and Ataxia to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Hereditary ataxia, adult onset v2.57 EBF3 Sarah Leigh Tag Q2_21_expert_review was removed from gene: EBF3.
Hereditary ataxia, adult onset v2.57 EBF3 Sarah Leigh changed review comment from: GMS review is requested in regard to Zornitza Stark's review; that the phenotype associated with EBF3 - Hypotonia, ataxia, and delayed development syndrome OMIM:617330 is not relevant to this panel as it is not an adult onset condtion.; to: The tag Q2_21_phenotype has been added to this gene, because variants in this gene are associated with childhood onset of ataxia in Hypotonia, ataxia, and delayed development syndrome OMIM:617330.
Early onset or syndromic epilepsy v2.361 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Intellectual disability v3.1094 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Intellectual disability v3.1094 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Hydrocephalus v2.101 ISLR2 Arina Puzriakova Publications for gene: ISLR2 were set to 30483960
Hydrocephalus v2.100 ISLR2 Arina Puzriakova Classified gene: ISLR2 as Red List (low evidence)
Hydrocephalus v2.100 ISLR2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family reported in PMID: 30483960 with congenital hydrocephalus, arthrogryposis and abdominal distension and a homozygous a frameshift deletion that segregated with disease. Knockout mouse model recapitulates some features of the human phenotype, i.e. hydrocephalus (PMID: 29739947).

Rating Red, awaiting further cases.
Hydrocephalus v2.100 ISLR2 Arina Puzriakova Gene: islr2 has been classified as Red List (Low Evidence).
Arthrogryposis v3.101 ISLR2 Arina Puzriakova Classified gene: ISLR2 as Red List (low evidence)
Arthrogryposis v3.101 ISLR2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family reported in PMID: 30483960 with congenital hydrocephalus, arthrogryposis and abdominal distension and a homozygous a frameshift deletion that segregated with disease. Knockout mouse model recapitulates some features of the human phenotype, i.e. hydrocephalus (PMID: 29739947).

Rating Red, awaiting further cases.
Arthrogryposis v3.101 ISLR2 Arina Puzriakova Gene: islr2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Intellectual disability v3.1094 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1093 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Intellectual disability v3.1093 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Intellectual disability v3.1092 UFSP2 Sarah Leigh Tag founder-effect tag was added to gene: UFSP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 IPO8 Boaz Palterer gene: IPO8 was added
gene: IPO8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604
Phenotypes for gene: IPO8 were set to cardiovascular anomalies; joint hyperlaxity; dysmorphic features; developmental delay; immune dysregulation; allergy
Penetrance for gene: IPO8 were set to unknown
Review for gene: IPO8 was set to GREEN
Added comment: Ziegler et al. reported 12 individuals from 9 unrelated kindreds with bi-allelic loss-of-function variants in IPO8 presenting with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation. IPO8 is involved in the TGFbeta/SMAD signaling, which is a known pathway in Loeys-Dietz syndrome. Functional data in a zebrafish model.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.38 GLRX5 Ivone Leong Tag Q2_21_rating tag was added to gene: GLRX5.
Hereditary spastic paraplegia, childhood onset v2.38 GLRX5 Ivone Leong Classified gene: GLRX5 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.38 GLRX5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Hereditary spastic paraplegia, childhood onset v2.38 GLRX5 Ivone Leong Gene: glrx5 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.37 GLRX5 Ivone Leong Phenotypes for gene: GLRX5 were changed from Spasticity, childhood-onset, with hyperglycinemia 616859 to Spasticity, childhood-onset, with hyperglycinemia, OMIM:616859
White matter disorders and cerebral calcification - childhood onset v1.104 GLRX5 Ivone Leong Tag Q2_21_rating tag was added to gene: GLRX5.
White matter disorders and cerebral calcification - childhood onset v1.104 GLRX5 Ivone Leong Classified gene: GLRX5 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.104 GLRX5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.104 GLRX5 Ivone Leong Gene: glrx5 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.103 GLRX5 Ivone Leong Phenotypes for gene: GLRX5 were changed from Spasticity, childhood-onset, with hyperglycinemia, MIM# 616859 to Spasticity, childhood-onset, with hyperglycinemia, OMIM:616859
White matter disorders and cerebral calcification - childhood onset v1.102 GLB1 Ivone Leong Classified gene: GLB1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.102 GLB1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene is also Green on the White matter disorders - adult onset (Version 1.11). There is enough evidence to support a gene-disease assocation. GM1-gangliosidosis affect those in their infancy and juvenile stages as well. Therefore this gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.102 GLB1 Ivone Leong Gene: glb1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.101 GLB1 Ivone Leong Tag Q2_21_rating tag was added to gene: GLB1.
White matter disorders and cerebral calcification - childhood onset v1.101 GLB1 Ivone Leong Phenotypes for gene: GLB1 were changed from GM1-gangliosidosis, type I, MIM# 230500; GM1-gangliosidosis, type II, MIM# 230600 to GM1-gangliosidosis, type I, OMIM:230500; GM1-gangliosidosis, type II, OMIM:230600
Early onset or syndromic epilepsy v2.361 UFSP2 Konstantinos Varvagiannis reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33473208; Phenotypes: Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1092 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Added comment: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability v3.1092 SIN3B Konstantinos Varvagiannis reviewed gene: SIN3B: Rating: AMBER; Mode of pathogenicity: None; Publications: 33811806; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia, adult onset v2.57 ERCC4 Sarah Leigh Tag Q2_21_rating tag was added to gene: ERCC4.
Hereditary ataxia, adult onset v2.57 ERCC4 Sarah Leigh commented on gene: ERCC4: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least nine variants reported in at least seven cases of Xeroderma pigmentosum, group F OMIM:278760, where neurodegeneration and ataxia was present (PMID 29403087; 28431612; 29892709).
Hereditary ataxia, adult onset v2.57 ERCC4 Sarah Leigh Phenotypes for gene: ERCC4 were changed from Cerebellar ataxia; Xeroderma pigmentosum, group F OMIM:278760; xeroderma pigmentosum group F MONDO:0010215 to Xeroderma pigmentosum, group F OMIM:278760; xeroderma pigmentosum group F MONDO:0010215
Hereditary ataxia, adult onset v2.56 ERCC4 Sarah Leigh Classified gene: ERCC4 as Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.56 ERCC4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary ataxia, adult onset v2.56 ERCC4 Sarah Leigh Gene: ercc4 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.55 ERCC4 Sarah Leigh Phenotypes for gene: ERCC4 were changed from Cerebellar ataxia; Xeroderma pigmentosum, group F, MIM# 278760 to Cerebellar ataxia; Xeroderma pigmentosum, group F OMIM:278760; xeroderma pigmentosum group F MONDO:0010215
Severe microcephaly v2.182 SASS6 Eleanor Williams Classified gene: SASS6 as Amber List (moderate evidence)
Severe microcephaly v2.182 SASS6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber as now two cases reported with severe microcephaly. Pubmed search did not find further cases at this time.
Severe microcephaly v2.182 SASS6 Eleanor Williams Gene: sass6 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.181 SASS6 Eleanor Williams Phenotypes for gene: SASS6 were changed from autosomal recessive primary microcephaly (MCPH); ?Microcephaly 14, primary, autosomal recessive, 616402 to ?Microcephaly 14, primary, autosomal recessive, OMIM:616402
Severe microcephaly v2.180 SASS6 Eleanor Williams edited their review of gene: SASS6: Changed phenotypes to: ?Microcephaly 14, primary, autosomal recessive, OMIM:616402
Severe microcephaly v2.180 SASS6 Eleanor Williams changed review comment from: Provisionally associated with ?Microcephaly 11, primary, autosomal recessive #615414 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.; to: Provisionally associated with ?Microcephaly 14, primary, autosomal recessive #616402 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.
Severe microcephaly v2.180 SASS6 Eleanor Williams Publications for gene: SASS6 were set to 24951542
Severe microcephaly v2.179 SASS6 Eleanor Williams reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 24951542, 30639237; Phenotypes: ?Microcephaly 11, primary, autosomal recessive, OMIM:615414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.179 RUSC2 Eleanor Williams Classified gene: RUSC2 as Red List (low evidence)
Severe microcephaly v2.179 RUSC2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red. 2 families reported with homozgyous nonsense variants in RUSC2 but the microcephaly phenotype is relatively mild although progressive.
Severe microcephaly v2.179 RUSC2 Eleanor Williams Gene: rusc2 has been classified as Red List (Low Evidence).
Severe microcephaly v2.178 RUSC2 Eleanor Williams reviewed gene: RUSC2: Rating: RED; Mode of pathogenicity: None; Publications: 27612186; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.178 PUS7 Eleanor Williams Tag Q2_21_rating tag was added to gene: PUS7.
Severe microcephaly v2.178 PUS7 Eleanor Williams Classified gene: PUS7 as Amber List (moderate evidence)
Severe microcephaly v2.178 PUS7 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review. 4 families reported with a severe microcephaly phenotype.
Severe microcephaly v2.178 PUS7 Eleanor Williams Gene: pus7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.177 PUS7 Eleanor Williams Phenotypes for gene: PUS7 were changed from Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM #618342 to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM:618342
Severe microcephaly v2.176 PUS7 Eleanor Williams reviewed gene: PUS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30526862, 30778726, 31583274; Phenotypes: Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM:618342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.176 PUF60 Eleanor Williams Classified gene: PUF60 as Amber List (moderate evidence)
Severe microcephaly v2.176 PUF60 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating at the next GMS review. 3 cases reported with heterozygous variants in PUF60 and a severe microcephaly phenotype.
Severe microcephaly v2.176 PUF60 Eleanor Williams Gene: puf60 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.175 PUF60 Eleanor Williams Phenotypes for gene: PUF60 were changed from Verheij syndrome, MIM# 615583 to Verheij syndrome, OMIM:615583
Severe microcephaly v2.174 PUF60 Eleanor Williams Publications for gene: PUF60 were set to 28327570
Severe microcephaly v2.173 PUF60 Eleanor Williams Tag Q2_21_rating tag was added to gene: PUF60.
Severe microcephaly v2.173 PUF60 Eleanor Williams reviewed gene: PUF60: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140112, 27804958, 28327570, 28074499, 28471317, 32851780; Phenotypes: Verheij syndrome, OMIM:615583; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.662 RFWD3 Arina Puzriakova Classified gene: RFWD3 as Red List (low evidence)
Fetal anomalies v1.662 RFWD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). To date, only a single patient has been reported in PMID: 28691929 - rating Red awaiting further cases.
Fetal anomalies v1.662 RFWD3 Arina Puzriakova Gene: rfwd3 has been classified as Red List (Low Evidence).
Fetal anomalies v1.661 RFWD3 Arina Puzriakova Publications for gene: RFWD3 were set to PMID: 2869192
Fetal anomalies v1.660 RFWD3 Arina Puzriakova Phenotypes for gene: RFWD3 were changed from Fanconi anaemia to ?Fanconi anemia, complementation group W, OMIM:617784
Fetal anomalies v1.659 FKBP8 Arina Puzriakova Mode of inheritance for gene: FKBP8 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.658 FKBP8 Arina Puzriakova Classified gene: FKBP8 as Amber List (moderate evidence)
Fetal anomalies v1.658 FKBP8 Arina Puzriakova Added comment: Comment on list classification: Additional publication identified by Rhiannon Mellis (GOSH) describing a fetus with severe thoracolumbar scoliosis and caudal spinal cord agenesis and a homozygous (c.C572T:p.P191L) variant in FKBP8 (PMID: 29261186). Note the phenotype and MOI are distinct from other reports (PMID: 32969478).

FKBP8 remains a candidate gene and so maintaining Amber rating in anticipation of additional cases to corroborate pathogenicity.
Fetal anomalies v1.658 FKBP8 Arina Puzriakova Gene: fkbp8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.657 FKBP8 Arina Puzriakova Phenotypes for gene: FKBP8 were changed from spina bifida HP:0002414 to Spina bifida, HP:0002414; Vertebral segmentation defects
Fetal anomalies v1.656 FKBP8 Arina Puzriakova Publications for gene: FKBP8 were set to 32969478
Fetal anomalies v1.655 PLD1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: PLD1.
Fetal anomalies v1.655 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 33645542
Fetal anomalies v1.654 PLD1 Arina Puzriakova Classified gene: PLD1 as Amber List (moderate evidence)
Fetal anomalies v1.654 PLD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Suzanne Drury (Congenica). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a fetally-relevant gene-disease association. This gene should be rated Green at the next review.
Fetal anomalies v1.654 PLD1 Arina Puzriakova Gene: pld1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.653 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from HP:0001654; HP:0001627; HP:0001638 to Cardiac valvular defect, developmental, OMIM:212093
Fetal anomalies v1.652 CLTC Arina Puzriakova reviewed gene: CLTC: Rating: ; Mode of pathogenicity: None; Publications: 33743358; Phenotypes: Mental retardation, autosomal dominant 56, OMIM:617854; Mode of inheritance: None
Fetal anomalies v1.652 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854; Fetal akinesia; Fetal growth restriction
Intellectual disability v3.1092 CAMK2B Arina Puzriakova Publications for gene: CAMK2B were set to
Severe microcephaly v2.173 CAMK2B Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAMK2B.
Severe microcephaly v2.173 CAMK2B Arina Puzriakova Publications for gene: CAMK2B were set to 32875707
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Classified gene: CAMK2B as Amber List (moderate evidence)
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Added comment: Comment on list classification: Gene added to this panel and rated Green by Zornitza Stark. Variable degree of microcephaly has been reported in 9/13 individuals with CAMK2B variants (PMIDs: 29100089; 29560374; 30842224; 32875707). Severe microcephaly (HC ≤ -3 SD) is reported in at least 4 unrelated individuals.

Overall sufficient cases to rate as Green on this panel. Inclusion may be particularly beneficial for cases with milder degree of DD/ID for which this gene is also Green.
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Gene: camk2b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.171 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from microcephaly; intellectual disability; behavioural problems to Mental retardation, autosomal dominant 54, OMIM:617799
Intellectual disability v3.1091 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from Mental retardation, autosomal dominant 54 617799 to Mental retardation, autosomal dominant 54, OMIM:617799
Neonatal diabetes v2.34 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Neonatal diabetes v2.34 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Diabetes - neonatal onset. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Early onset or syndromic epilepsy v2.361 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Early onset or syndromic epilepsy v2.361 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Intellectual disability v3.1090 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Intellectual disability v3.1090 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: YIPF5.
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Classified gene: YIPF5 as Amber List (moderate evidence)
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Added comment: Comment on list classification: New gene added and rated Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (all affected individuals present progressive severe microcephaly, generalised tonic clonic seizures with onset at 1 - 7 months, diabetes diagnosed at 4 weeks - 15 months, and 5/6 also had severe DD) for inclusion on this panel: 6 patients from 5 families with different YIPF5 variants identified in PMID: 33164986. Functional analysis demonstrated that YIPF5 deficiency enhances ER stress and sensitises beta-cells to ER stress-induced apoptosis.

YIPF5 is also associated with a relevant phenotype in OMIM (MIM# 619278) but is not yet listed in G2P.

There is enough evidence to rate this gene as Green at the next GMS panel update.
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Gene: yipf5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.169 YIPF5 Arina Puzriakova Phenotypes for gene: YIPF5 were changed from Neonatal diabetes; microcephaly; seizures to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Severe microcephaly v2.168 RRP7A Arina Puzriakova Classified gene: RRP7A as Amber List (moderate evidence)
Severe microcephaly v2.168 RRP7A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33199730 report a homozygous missense variant (c.465G>C; p.Trp155Cys) in RRP7A that segregated with primary microcephaly in a consanguineous family with 10 affected individuals. Supported by animal model data. Rating Amber, awaiting further cases.
Severe microcephaly v2.168 RRP7A Arina Puzriakova Gene: rrp7a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.37 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Mitochondrial disorders v2.37 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Mitochondrial disorders. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Mitochondrial DNA maintenance disorder v1.4 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Mitochondrial DNA maintenance disorder v1.4 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Mitochondrial DNA maintenance disorder. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Possible mitochondrial disorder, nuclear genes v1.43 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Possible mitochondrial disorder, nuclear genes v1.43 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Possible mitochondrial disorder - nuclear genes. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Ataxia and cerebellar anomalies - childhood onset v2.183 LIG3 Ivone Leong Tag watchlist tag was added to gene: LIG3.
Ataxia and cerebellar anomalies - childhood onset v2.183 LIG3 Ivone Leong edited their review of gene: LIG3: Added comment: As only 1 family has signs of ataxia and the knockout mouse model recapitulated this phenotype this gene has been given an Amber rating on this panel.; Changed rating: AMBER
Ataxia and cerebellar anomalies - childhood onset v2.183 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Retinal disorders v2.186 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Tag watchlist tag was added to gene: LIG3.
Retinal disorders v2.186 LIG3 Ivone Leong edited their review of gene: LIG3: Added comment: As only 2 affected families have macular degeneration this gene has been given an Amber rating until more evidence is available.; Changed rating: AMBER
Ataxia and cerebellar anomalies - childhood onset v2.183 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Ataxia and cerebellar anomalies - childhood onset v2.183 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Retinal disorders v2.186 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Retinal disorders v2.186 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Retinal disorders. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Intellectual disability v3.1089 UNC80 Arina Puzriakova Publications for gene: UNC80 were set to 25529582; 2670875126708753
Inherited white matter disorders v1.97 LIG3 Ivone Leong Classified gene: LIG3 as Green List (high evidence)
Inherited white matter disorders v1.97 LIG3 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my previous review.
Inherited white matter disorders v1.97 LIG3 Ivone Leong Gene: lig3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.360 UNC80 Arina Puzriakova Publications for gene: UNC80 were set to 26545877; 26708753; 26708751
Inherited white matter disorders v1.96 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Gastrointestinal neuromuscular disorders v1.14 LIG3 Ivone Leong Classified gene: LIG3 as Green List (high evidence)
Gastrointestinal neuromuscular disorders v1.14 LIG3 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my previous review.
Gastrointestinal neuromuscular disorders v1.14 LIG3 Ivone Leong Gene: lig3 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disorders v1.13 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Leukodystrophy, adult onset v1.11 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Leukodystrophy, adult onset v1.11 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to White matter disorders - adult onset. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Severe microcephaly v2.167 UNC80 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UNC80.
Severe microcephaly v2.167 UNC80 Arina Puzriakova Classified gene: UNC80 as Amber List (moderate evidence)
Severe microcephaly v2.167 UNC80 Arina Puzriakova Added comment: Comment on list classification: Gene added to panel and rated Green by Zornitza Stark. Variable degrees reported but there are enough unrelated cases (>3) with sufficiently severe microcephaly and distinct UNC80 variants to rate as Green on this panel.
Severe microcephaly v2.167 UNC80 Arina Puzriakova Gene: unc80 has been classified as Amber List (Moderate Evidence).
Gastrointestinal neuromuscular disorders v1.13 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Gastrointestinal neuromuscular disorders v1.13 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Gastrointestinal neuromuscular disorders. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Inherited white matter disorders v1.96 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Inherited white matter disorders v1.96 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Inherited white matter disorders. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
White matter disorders and cerebral calcification - childhood onset v1.100 LIG3 Ivone Leong Tag Q2_21_rating tag was added to gene: LIG3.
White matter disorders and cerebral calcification - childhood onset v1.100 LIG3 Ivone Leong Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
White matter disorders and cerebral calcification - childhood onset v1.99 LIG3 Ivone Leong Classified gene: LIG3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.99 LIG3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:33855352. 3 unrelated families with 7 affected individuals. Clinical features of affected individuals resemble mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). All had severe dysmotility of the gut, leukoencephalopathy and/or progressive cortical atrophy. Cerebella atrophy was only seen in patients in family 3. Other neurological features were epilepsy, stroke-like episodes, migraine and developmental delay. 4 members from families 1 and 2 had macular degeneration, 1 member from family 3 had cataracts and hearing loss. Age of onset and disease severity differed, ranging from paediatric severe disease with premature death to adult cases. All affected members from the 3 families were compound heterozygous for different LIG3 variants.

LIG3 variants cause impared ligase activity, mtDNA depletion and mitochondrial dysfunction.

The authors also created a zebrafish model, which recapitulated the cerebellar phenotype (seen in mice) and eye defects and gut propulsion impairment (seen in patients). Knockdown of lig3 in zf also led to decrease in expression of mitochondrial markers.

Knocking out Lig3 in mice led to early embryonic lethality with mitochondrial dysfunction due to reduced mtDNA in the nervous system (PMID: 21390131); however, gut motility was not investigated in these mice.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.99 LIG3 Ivone Leong Gene: lig3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1088 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Severe microcephaly v2.166 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 MIM#616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Early onset or syndromic epilepsy v2.359 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Severe microcephaly v2.165 UGP2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UGP2.
Severe microcephaly v2.165 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Severe microcephaly v2.165 UGP2 Arina Puzriakova Added comment: Comment on list classification: Gene added to panel and rated Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (progressive microcephaly seen in all patients with available data) for inclusion on panel: 22 patients from 15 families all with the same variant identified in PMID:31820119. Therefore there is sufficient evidence to rate this gene as Green at the next GMS panel update.
Severe microcephaly v2.165 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.118 FUCA1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FUCA1.
Dystonia, chorea or related movement disorder, childhood onset v1.118 FUCA1 Sarah Leigh Classified gene: FUCA1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.118 FUCA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.118 FUCA1 Sarah Leigh Gene: fuca1 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.117 FUCA1 Sarah Leigh reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.164 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy; intellectual disability; microcephaly to Developmental and epileptic encephalopathy 83, OMIM:618744
Intellectual disability v3.1087 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Developmental and epileptic encephalopathy 83, OMIM:618744
Early onset or syndromic epilepsy v2.358 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; seizures to Developmental and epileptic encephalopathy 83, OMIM:618744
Dystonia, chorea or related movement disorder, childhood onset v1.117 FUCA1 Sarah Leigh Phenotypes for gene: FUCA1 were changed from to Fucosidosis OMIM:230000; fucosidosis MONDO:0009254
Dystonia, chorea or related movement disorder, childhood onset v1.116 FUCA1 Sarah Leigh Publications for gene: FUCA1 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.115 FUCA1 Sarah Leigh Mode of inheritance for gene: FUCA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.114 C9orf72 Sarah Leigh reviewed gene: C9orf72: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.114 C9orf72 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: C9orf72.
Tag Q2_21_expert_review tag was added to gene: C9orf72.
Hereditary ataxia, adult onset v2.54 EBF3 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: EBF3.
Tag Q2_21_expert_review tag was added to gene: EBF3.
Hereditary ataxia, adult onset v2.54 EBF3 Sarah Leigh reviewed gene: EBF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.54 EBF3 Sarah Leigh Publications for gene: EBF3 were set to
Intellectual disability v3.1086 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 0
Intellectual disability v3.1085 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Hereditary ataxia, adult onset v2.53 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia 5, 610204; Pontocerebellar hypoplasia 4, 225753; Pontocerebellar hypoplasia 2A, 277470; Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar hypoplasia type 2A, 277470 to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Hereditary ataxia, adult onset v2.52 ATP8A2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ATP8A2.
Tag Q2_21_expert_review tag was added to gene: ATP8A2.
Hereditary ataxia, adult onset v2.52 ATP8A2 Sarah Leigh changed review comment from: Zornitza Stark has commented this gene is responsible for a congenital condition and not for an adult onset phenotype. However, table 1 in PMID 31612321 provides a review of the reported variants and their associated clinical features, where a few cases occur after adolescence. This provides justification for this gene being green on this adult onset panel.; to: Zornitza Stark has commented this gene is responsible for a congenital condition and not for an adult onset phenotype. However, table 1 in PMID 31612321 provides a review of the reported variants and their associated clinical features, where a few cases occur after adolescence. This provides some justification for this gene being green on this adult onset panel.
Early onset or syndromic epilepsy v2.357 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 20956791; 7854532; 26701950; 20952379
Early onset or syndromic epilepsy v2.356 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar hypoplasia type 2A, 277470; ?Pontocerebellar hypoplasia type 5, 610204 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Fetal anomalies v1.651 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to
Fetal anomalies v1.650 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4; Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar hypoplasia type 4, 225753 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Arthrogryposis v3.100 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 4 225753 to Pontocerebellar hypoplasia type 4, OMIM:225753
Arthrogryposis v3.99 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to
Hereditary ataxia, adult onset v2.52 ATP8A2 Sarah Leigh reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.223 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar hypoplasia type 4, 225753 to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Ataxia and cerebellar anomalies - childhood onset v2.182 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to PMID: 20956791; PMID: 18711368; PMID: 20952379; PMID: 21368912
Cerebellar hypoplasia v1.48 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 18711368; 20956791; 20952379; 20301773
Ataxia and cerebellar anomalies - childhood onset v2.181 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar Hypoplasia type 2A; Pontocerebellar hypoplasia 2A (#277470) and 4 (#225753); Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar Hypoplasia type 4; Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar Hypoplasia; Pontocerebellar Hypoplasia type 5 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Rhabdomyolysis and metabolic muscle disorders v1.46 TSEN54 Arina Puzriakova Classified gene: TSEN54 as Green List (high evidence)
Rhabdomyolysis and metabolic muscle disorders v1.46 TSEN54 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel review - only a single patient reported to date, with rhabdomyolysis and a homozygous TSEN54 variant.
Rhabdomyolysis and metabolic muscle disorders v1.46 TSEN54 Arina Puzriakova Gene: tsen54 has been classified as Green List (High Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.45 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from ?Pontocerebellar hypoplasia type 5 610204; Pontocerebellar hypoplasia type 2A 277470; Pontocerebellar hypoplasia type 4 225753 to Pontocerebellar hypoplasia type 2A, OMIM:277470
Rhabdomyolysis and metabolic muscle disorders v1.44 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 25929793; 18711368
Rhabdomyolysis and metabolic muscle disorders v1.43 TSEN54 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN54.
Rhabdomyolysis and metabolic muscle disorders v1.43 TSEN54 Arina Puzriakova reviewed gene: TSEN54: Rating: RED; Mode of pathogenicity: None; Publications: 23177318; Phenotypes: Pontocerebellar hypoplasia type 2A, OMIM:277470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.114 C9orf72 James Polke reviewed gene: C9orf72: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.114 CSTB Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CSTB.
Dystonia, chorea or related movement disorder, childhood onset v1.114 CSTB Sarah Leigh reviewed gene: CSTB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, childhood onset v2.36 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Hereditary spastic paraplegia, childhood onset v2.36 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Inherited white matter disorders v1.95 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Inherited white matter disorders v1.95 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Inherited white matter disorders. Sources: Expert Review Amber,Literature
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Hereditary spastic paraplegia v1.222 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Hereditary spastic paraplegia v1.222 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Literature
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Hereditary ataxia v1.222 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Hereditary ataxia v1.222 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary ataxia. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Ataxia and cerebellar anomalies - childhood onset v2.180 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Ataxia and cerebellar anomalies - childhood onset v2.180 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Cerebellar hypoplasia v1.47 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to PMID: 21368912; PMID: 18711368; PMID: 20956791; PMID: 20952379;
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN54.
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Classified gene: TSEN54 as Amber List (moderate evidence)
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Progressive microcephaly is a feature associated with PCH types 2 and 4. Sufficient number of unrelated cases (>3) to rate this gene as Green at the next GMS panel review.
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Gene: tsen54 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.162 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 20952379; 20301773
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Tag watchlist tag was added to gene: POLR3K.
Tag founder-effect tag was added to gene: POLR3K.
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Classified gene: POLR3K as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype.

PMID: 30584594. 2 affected individuals from 2 consanguineous families from same area in Algeria. Affected indviduals had global developmental delay with loss of motor, speech and cognitive milestones. Individuals also showed signs of nystagmus, ataxia, dystonia and spasticity. Both individuals had feeding difficulties and were tube fed, growth failure and microcephaly (-3 SD), and cryptorchidism. 1 patient had optic atrophy and hypodontia and the other patient had hypogonadotropic hypogonadism. Both individuals have the same variant (may be founder effect).

As other members of the same gene family are linked to similar phenotypes this gene has been given an Amber rating.
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Gene: polr3k has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.35 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1084 AFG3L2 Sarah Leigh commented on gene: AFG3L2: Disease causing variants are both monoallelic and biallelic
Intellectual disability v3.1084 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Hereditary spastic paraplegia, childhood onset v2.35 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
Intellectual disability v3.1083 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
Intellectual disability v3.1083 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.221 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive; Spastic ataxia 5, autosomal recessive to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Hereditary spastic paraplegia v1.220 AFG3L2 Sarah Leigh Mode of inheritance for gene: AFG3L2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.46 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar Hypoplasia type 5; Pontocerebellar Hypoplasia type 2A; Pontocerebellar Hypoplasia type 4; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar hypoplasia type 4, 225753 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Severe microcephaly v2.161 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753) to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
White matter disorders and cerebral calcification - childhood onset v1.97 POLR3K Ivone Leong Phenotypes for gene: POLR3K were changed from Hypomyelinating leukodystrophy-21, MIM#619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310
White matter disorders and cerebral calcification - childhood onset v1.96 LSM7 Ivone Leong Classified gene: LSM7 as Red List (low evidence)
White matter disorders and cerebral calcification - childhood onset v1.96 LSM7 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Currently there is not enough evidence to support a gene-disease association. Until there are more cases this gene has been given a Red rating.
White matter disorders and cerebral calcification - childhood onset v1.96 LSM7 Ivone Leong Gene: lsm7 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.95 LSM7 Ivone Leong Phenotypes for gene: LSM7 were changed from Leukodystrophy; fetal death to Leukodystrophy, MONDO:0019046
Hereditary spastic paraplegia, adult onset v1.21 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive; Ataxia, spastic, 5, autosomal recessive; Spinocerebellar ataxia 28, autosomal dominant, 610246 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Hereditary ataxia, adult onset v2.52 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spinocerebellar ataxia 28, 610246; Ataxia, spastic, 5, autosomal recessive; spastic ataxia 5, 614487; Spinocerebellar ataxia 28; Spinocerebellar Ataxia, Dominant to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Mitochondrial disorders v2.36 AFG3L2 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity
Mitochondrial disorders v2.36 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Spinocerebellar ataxia 28, 610246; Ataxia, spastic, 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Likely inborn error of metabolism v2.135 AFG3L2 Sarah Leigh Added comment: Comment on phenotypes: Ataxia, spastic, 5, autosomal recessive, 614487;Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only));Spinocerebellar ataxia 28, 610246;Disorders of mitochondrial DNA maintenance and integrity
Likely inborn error of metabolism v2.135 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive, 614487; Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spinocerebellar ataxia 28, 610246; Disorders of mitochondrial DNA maintenance and integrity to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Hereditary spastic paraplegia, childhood onset v2.35 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive; Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Dystonia, chorea or related movement disorder, childhood onset v1.114 AFG3L2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AFG3L2.
Hereditary spastic paraplegia, adult onset v1.20 AFG3L2 Sarah Leigh commented on gene: AFG3L2
Hereditary spastic paraplegia, adult onset v1.20 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
Hereditary spastic paraplegia, adult onset v1.20 AFG3L2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AFG3L2.
Dystonia, chorea or related movement disorder, childhood onset v1.114 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to 22964162; 16541453; 32219868
Dystonia, chorea or related movement disorder, childhood onset v1.113 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to 22964162; 1654145; 332219868
Dystonia, chorea or related movement disorder, childhood onset v1.112 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to 22964162; 1654145332219868
Dystonia, chorea or related movement disorder, childhood onset v1.111 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to
Cerebellar hypoplasia v1.45 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Cerebellar hypoplasia v1.45 TSEN15 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber - PMID:27392077 report on 2 families with PCH and biallelic variants in this gene (brain MRI was not available in third family). Additional cases required prior to inclusion as diagnostic-grade.
Cerebellar hypoplasia v1.45 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.179 TSEN15 Arina Puzriakova Tag watchlist tag was added to gene: TSEN15.
Ataxia and cerebellar anomalies - childhood onset v2.179 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.179 TSEN15 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber - PMID:27392077 report on 2 families with PCH and biallelic variants in this gene (brain MRI was not available in third family). Additional cases required prior to inclusion as diagnostic-grade (added watchlist tag)
Ataxia and cerebellar anomalies - childhood onset v2.179 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.51 TSEN15 Arina Puzriakova Publications for gene: TSEN15 were set to
Hereditary ataxia, adult onset v2.50 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Green List (high evidence)
Hereditary ataxia, adult onset v2.50 TSEN15 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel review
Hereditary ataxia, adult onset v2.50 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Green List (High Evidence).
Hereditary ataxia, adult onset v2.49 TSEN15 Arina Puzriakova reviewed gene: TSEN15: Rating: RED; Mode of pathogenicity: None; Publications: 27392077; Phenotypes: Pontocerebellar hypoplasia, type 2F, OMIM:617026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.49 TSEN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN15.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN15.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Added comment: Comment on list classification: TSEN15 was added and rated Green by Zornitza Stark based on PMID:27392077 (Breuss et al, 2016) who report three homozygous TSEN15 variants in four individuals from three families. All affected individuals developed progressive microcephaly of relevant severity, which represented an early and main feature of the disease presentation.

There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.159 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F MIM#617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Dystonia, chorea or related movement disorder, childhood onset v1.110 C9orf72_GGGGCC Sarah Leigh Deleted their review
Dystonia, chorea or related movement disorder, adult onset v1.114 C9orf72_GGGGCC Sarah Leigh Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Dystonia, chorea or related movement disorder, childhood onset v1.110 C9orf72_GGGGCC Sarah Leigh Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Dystonia, chorea or related movement disorder, childhood onset v1.109 C9orf72 Sarah Leigh Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Dystonia, chorea or related movement disorder, childhood onset v1.108 C9orf72 Sarah Leigh Publications for gene: C9orf72 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.107 C9orf72_GGGGCC Sarah Leigh Tag Q2_21_rating tag was added to STR: C9orf72_GGGGCC.
Dystonia, chorea or related movement disorder, childhood onset v1.107 C9orf72_GGGGCC Sarah Leigh Classified STR: C9orf72_GGGGCC as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.107 C9orf72_GGGGCC Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.107 C9orf72_GGGGCC Sarah Leigh Str: c9orf72_ggggcc has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.106 C9orf72_GGGGCC Sarah Leigh Entity copied from Adult onset movement disorder v1.113
Dystonia, chorea or related movement disorder, childhood onset v1.106 C9orf72_GGGGCC Sarah Leigh STR: C9orf72_GGGGCC was added
STR: C9orf72_GGGGCC was added to Childhood onset dystonia or chorea or related movement disorder. Sources: NHS GMS,Expert Review Green,London North GLH,Expert list
STR tags were added to STR: C9orf72_GGGGCC.
Mode of inheritance for STR: C9orf72_GGGGCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: C9orf72_GGGGCC were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550
Hereditary spastic paraplegia, childhood onset v2.34 HPDL Sarah Leigh Publications for gene: HPDL were set to 32707086; 33188300
Hereditary ataxia, adult onset v2.49 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia 2F, 617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Intellectual disability v3.1083 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from delayed developmental milestones; Pontocerebellar hypoplasia, type 2F, 617026; Intellectual disability to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Early onset or syndromic epilepsy v2.355 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F, 617026; seizures to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Cerebellar hypoplasia v1.44 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F 617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Ataxia and cerebellar anomalies - childhood onset v2.178 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F 617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Ataxia and cerebellar anomalies - childhood onset v2.177 TSEN15 Arina Puzriakova reviewed gene: TSEN15: Rating: ; Mode of pathogenicity: None; Publications: 27392077; Phenotypes: Pontocerebellar hypoplasia, type 2F, OMIM:617026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.99 LTBP1 Sarah Leigh Classified gene: LTBP1 as Amber List (moderate evidence)
Skeletal dysplasia v2.99 LTBP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal dysplasia v2.99 LTBP1 Sarah Leigh Gene: ltbp1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.98 LTBP1 Sarah Leigh gene: LTBP1 was added
gene: LTBP1 was added to Skeletal dysplasia. Sources: Literature
Q2_21_rating tags were added to gene: LTBP1.
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to inherited cutis laxa MONDO:0100237
Review for gene: LTBP1 was set to GREEN
Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (as of 18/05/20210). At least four terminating variants were reported in unrelated cases. Supportive in vitro and in vivo studies demonstrate the role of LTBP1 in skin and bone ECM assembly and homeostasis, in human and zebrafish (PMID 33991472).
Sources: Literature
Intellectual disability v3.1082 TRIO Arina Puzriakova Publications for gene: TRIO were set to 0
Severe microcephaly v2.158 TRIO Arina Puzriakova Classified gene: TRIO as Amber List (moderate evidence)
Severe microcephaly v2.158 TRIO Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green status at the next GMS panel update - microcephaly of relevant severity to this panel is observed in at least 12 unrelated families with TRIO variants. Pathogenicity is supported by functional data and animal model.
Severe microcephaly v2.158 TRIO Arina Puzriakova Gene: trio has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.157 TRIO Arina Puzriakova Publications for gene: TRIO were set to 26721934; 32109419
Severe microcephaly v2.156 TRIO Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRIO.
Severe microcephaly v2.156 TRIO Arina Puzriakova Phenotypes for gene: TRIO were changed from Mental retardation, autosomal dominant 44, MIM# 617061 to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061
Intellectual disability v3.1081 TRIO Arina Puzriakova Phenotypes for gene: TRIO were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061; Intellectual developmental disorder, autosomal dominant 63, with macrocephaly, OMIM:618825
Ataxia and cerebellar anomalies - childhood onset v2.177 VRK1 Arina Puzriakova Phenotypes for gene: VRK1 were changed from Pontocerebellar Hypoplasia type 1A; Pontocerebellar Hypoplasia with infantile SMA; Pontocerebellar Hypoplasia with anterior horn cell disease; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia 1A (#607596); Pontocerebellar hypoplasia type 1A,607596 to Pontocerebellar hypoplasia type 1A, OMIM:607596
Ataxia and cerebellar anomalies - childhood onset v2.176 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia 5 (AD); Spinocerebellar ataxia, autosomal recessive 14; SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14; Spinocerebellar Ataxia, Dominant; Spinocerebellar ataxia, autosomal recessive 14 (AR); Spinocerebellar ataxia 5; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant) to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Primary ovarian insufficiency v1.43 FANCM Ivone Leong Classified gene: FANCM as Green List (high evidence)
Primary ovarian insufficiency v1.43 FANCM Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence for this gene to be rated Green.
Primary ovarian insufficiency v1.43 FANCM Ivone Leong Gene: fancm has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.42 FANCM Ivone Leong Phenotypes for gene: FANCM were changed from Premature ovarian failure to ?Premature ovarian failure 15, OMIM:618096
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Tag watchlist tag was added to gene: EIF4ENIF1.
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Classified gene: EIF4ENIF1 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Added comment: Comment on list classification: Gene is not assiciated with a phenotype in OMIM or Gene2Phenotype. Gene will be kept as Amber until more evidence is available.
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Gene: eif4enif1 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.40 EIF4ENIF1 Ivone Leong Deleted their review
Primary ovarian insufficiency v1.40 NANOS3 Ivone Leong Added comment: Comment on publications: Added new publication.
Primary ovarian insufficiency v1.40 NANOS3 Ivone Leong Publications for gene: NANOS3 were set to 24091668; 25054146; 28076512
Primary ovarian insufficiency v1.39 NANOS3 Ivone Leong Publications for gene: NANOS3 were set to 24091668; 25054146
Primary ovarian insufficiency v1.38 NANOS3 Ivone Leong Publications for gene: NANOS3 were set to 24091668
Primary ovarian insufficiency v1.37 MSH4 Ivone Leong Classified gene: MSH4 as Green List (high evidence)
Primary ovarian insufficiency v1.37 MSH4 Ivone Leong Gene: msh4 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.36 MSH4 Ivone Leong gene: MSH4 was added
gene: MSH4 was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: MSH4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSH4 were set to 28541421; 10809667; 33437391; 33448284
Phenotypes for gene: MSH4 were set to Primary ovarian insufficiency; primary ovarian failure, MONDO:0005387; non-obstructive azoospermia
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:28541421. 1 family affected by POI (NM_002440.3: c.2355+1G>A). Parents are heterozygous for the variant and 2 daughters (3 daughters and 2 sons in total) are homozygous for variant and diagnosed with POI. Variant causes exon skipping.

PMID:10809667. Msh4 knockout mouse model. Mice were viable except for low testicular weight. -/- males were infertile. -/- females, most oocytes were lost from ovaries shortly after birth.

PMID:33437391. Han Chinese patient with non-obstructive azoospermia (NOA) from a consanguineous family. Patient had homozygous variant in MSH4 (c.1552C>T:p.Q518X) and parents are heterozygous carriers.

PMID:33448284. Consanguineous family with 14 children. 2 women have been diagnosed with POI, 3 men with NOA and 1 man with oligozoospermia. All affected individuals are homozygous for variant in MSH4 (S754L).

There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Sources: Literature
Clefting v2.30 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to 20004764
Intellectual disability v3.1080 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to
Severe microcephaly v2.155 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to 22549410; 20004765; 20004763; 30853973
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRAPPC9.
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Classified gene: TRAPPC9 as Amber List (moderate evidence)
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 32 affected individuals from 9 families have been reported worldwide. Variable degrees of microcephaly are reported in almost all subjects and there are enough unrelated cases with sufficiently severe microcephaly to include as diagnostic-grade on this panel.
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Gene: trappc9 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.174 FIG4 Ian Berry reviewed gene: FIG4: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 19118816; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ectodermal dysplasia v1.19 SNRPE Gavin Ryan reviewed gene: SNRPE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.153 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, MIM# 613192 to Mental retardation, autosomal recessive 13, OMIM:613192
Intellectual disability v3.1079 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, 613192; Mental Retardation, Recessive; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 13 (MRT13) to Mental retardation, autosomal recessive 13, OMIM:613192
Clefting v2.29 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 13; MRT13 to Mental retardation, autosomal recessive 13, OMIM:613192
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRAPPC6B.
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Intellectual disability v3.1078 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Early onset or syndromic epilepsy v2.354 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Early onset or syndromic epilepsy v2.353 TRAPPC6B Arina Puzriakova Publications for gene: TRAPPC6B were set to 28626029; 28397838; DOI 10.1055/s-0039-1693664
Intellectual disability v3.1077 TRAPPC6B Arina Puzriakova Publications for gene: TRAPPC6B were set to 28626029; 28397838
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Classified gene: TRAPPC6B as Amber List (moderate evidence)
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 9 individuals from 5 families have been reported, all harbouring loss-of-function variants in homozygous state. Progressive microcephaly of relevant severity to this panel (HC ≤ -3 SD) was reported in 7/7 cases (clinical details limited for one family).

TRAPPC6B is associated with a relevant phenotype in OMIM (MIM# 617862)
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Tag watchlist tag was added to gene: MSH5.
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Classified gene: MSH5 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Gene: msh5 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.34 MSH5 Ivone Leong Phenotypes for gene: MSH5 were changed from ?Premature ovarian failure 13 617442 to ?Premature ovarian failure 13, OMIM:617442
Primary ovarian insufficiency v1.33 MSH5 Ivone Leong Publications for gene: MSH5 were set to 28175301
Primary ovarian insufficiency v1.32 EIF4ENIF1 Ivone Leong Classified gene: EIF4ENIF1 as Green List (high evidence)
Primary ovarian insufficiency v1.32 EIF4ENIF1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is 3 unrelated cases associated with this gene, therefore there is enough evidence to support a gene-disease association.
Primary ovarian insufficiency v1.32 EIF4ENIF1 Ivone Leong Gene: eif4enif1 has been classified as Green List (High Evidence).
Clefting v2.28 SEPT9 Zornitza Stark reviewed gene: SEPT9: Rating: AMBER; Mode of pathogenicity: None; Publications: 18492087; Phenotypes: Amyotrophy, hereditary neuralgic, MIM# 162100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.105 FXN_GAA Sarah Leigh changed review comment from: The FXN expansion has a well recognized association with Friedreich ataxia OMIM:229300; to: The FXN expansion has a well recognized association with Friedreich ataxia OMIM:229300

Comment from Zornitza Stark for FXN:
Primarily an ataxia, and also commonly caused by a GAA trinucleotide repeat expansion in intron 1 of the FXN gene.
Primary ovarian insufficiency v1.31 EIF4ENIF1 Ivone Leong Publications for gene: EIF4ENIF1 were set to 23902945
Primary ovarian insufficiency v1.30 DIAPH2 Ivone Leong Classified gene: DIAPH2 as Red List (low evidence)
Primary ovarian insufficiency v1.30 DIAPH2 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert review.
Primary ovarian insufficiency v1.30 DIAPH2 Ivone Leong Gene: diaph2 has been classified as Red List (Low Evidence).
Primary ovarian insufficiency v1.29 DIAPH2 Ivone Leong Phenotypes for gene: DIAPH2 were changed from Premature ovarian failure,300511 to ?Premature ovarian failure 2A, OMIM:300511
Primary ovarian insufficiency v1.28 DIAPH2 Ivone Leong Publications for gene: DIAPH2 were set to 9497258
Primary ovarian insufficiency v1.27 HSF2BP Ivone Leong Classified gene: HSF2BP as Red List (low evidence)
Primary ovarian insufficiency v1.27 HSF2BP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support gene-disease association. This gene has been given a Red rating.
Primary ovarian insufficiency v1.27 HSF2BP Ivone Leong Gene: hsf2bp has been classified as Red List (Low Evidence).
Primary ovarian insufficiency v1.26 HSF2BP Ivone Leong Phenotypes for gene: HSF2BP were changed from Premature ovarian failure, OMIM#619245 to Premature ovarian failure 19, OMIM:619245
Primary ovarian insufficiency v1.25 C14orf39 Ivone Leong Classified gene: C14orf39 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.25 C14orf39 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.25 C14orf39 Ivone Leong Gene: c14orf39 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.24 C14orf39 Ivone Leong Phenotypes for gene: C14orf39 were changed from Premature ovarian insufficiency to ?Premature ovarian failure 18, OMIM:619203
Primary ovarian insufficiency v1.23 BUB1B Ivone Leong Classified gene: BUB1B as Amber List (moderate evidence)
Primary ovarian insufficiency v1.23 BUB1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.23 BUB1B Ivone Leong Gene: bub1b has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection v1.114 PKD2 Ivone Leong Classified gene: PKD2 as Red List (low evidence)
Thoracic aortic aneurysm or dissection v1.114 PKD2 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert reviews. This gene is also Red on the Thoracic aortic aneurysm and dissection (Version 1.7) panel.
Thoracic aortic aneurysm or dissection v1.114 PKD2 Ivone Leong Gene: pkd2 has been classified as Red List (Low Evidence).
Thoracic aortic aneurysm or dissection v1.113 PKD1 Ivone Leong Classified gene: PKD1 as Red List (low evidence)
Thoracic aortic aneurysm or dissection v1.113 PKD1 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert reviews. This gene is also Red on the Thoracic aortic aneurysm and dissection (Version 1.7) panel.
Thoracic aortic aneurysm or dissection v1.113 PKD1 Ivone Leong Gene: pkd1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.94 ACER3 Ivone Leong Classified gene: ACER3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.94 ACER3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
White matter disorders and cerebral calcification - childhood onset v1.94 ACER3 Ivone Leong Gene: acer3 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.93 ACER3 Ivone Leong Tag watchlist tag was added to gene: ACER3.
White matter disorders and cerebral calcification - childhood onset v1.93 ACER3 Ivone Leong Phenotypes for gene: ACER3 were changed from Leukodystrophy to ?Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Dystonia, chorea or related movement disorder, childhood onset v1.105 FXN_GAA Sarah Leigh Tag Q2_21_rating tag was added to STR: FXN_GAA.
Dystonia, chorea or related movement disorder, childhood onset v1.105 FXN_GAA Sarah Leigh edited their review of STR: FXN_GAA: Added comment: The FXN expansion has a well recognized association with Friedreich ataxia OMIM:229300; Changed rating: GREEN; Changed publications to: 10399865, 8596916, 33670433
Dystonia, chorea or related movement disorder, childhood onset v1.105 FXN_GAA Sarah Leigh Classified STR: FXN_GAA as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.105 FXN_GAA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.105 FXN_GAA Sarah Leigh Str: fxn_gaa has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.104 FXN_GAA Sarah Leigh Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.175
Dystonia, chorea or related movement disorder, childhood onset v1.104 FXN_GAA Sarah Leigh STR: FXN_GAA was added
STR: FXN_GAA was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list,Expert Review Green
STR tags were added to STR: FXN_GAA.
Mode of inheritance for STR: FXN_GAA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for STR: FXN_GAA were set to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Severe microcephaly v2.150 PTPN23 Eleanor Williams changed review comment from: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly confirmed in 2 cases, a further 3 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.; to: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly (OFC > 3 SD below mean) confirmed in 1 case, a further 4 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.
Severe microcephaly v2.150 PTPN23 Eleanor Williams reviewed gene: PTPN23: Rating: AMBER; Mode of pathogenicity: None; Publications: 31395947, 29899372, 29090338, 27848944, 25558065; Phenotypes: Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, OMIM:618890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.175 MTCL1 Arina Puzriakova Classified gene: MTCL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.175 MTCL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update - two unrelated individuals with different LoF variants in this gene. Ataxia with cerebellar atrophy was the predominant presentation in both cases (PMIDs: 30548255; 32961396). Knockout animal model recapitulates human phenotypes and provides functional support.
Ataxia and cerebellar anomalies - childhood onset v2.175 MTCL1 Arina Puzriakova Gene: mtcl1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.174 MTCL1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MTCL1.
Ataxia and cerebellar anomalies - childhood onset v2.174 MTCL1 Arina Puzriakova reviewed gene: MTCL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30548255, 32961396; Phenotypes: Cerebellar ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v2.57 LTBP2 Andžela Lazdāne changed review comment from: Based on the literature several individuals were suspected of marfan syndrome. Not only due to eye changes, but also due to stature, increased arm span and decreased upper-to-lower body ratio.
Sources: Literature; to: Based on the literature several individuals were suspected of Marfan syndrome. Not only due to eye changes, but also due to stature, increased arm span and decreased upper-to-lower body ratio.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v2.57 LTBP2 Andžela Lazdāne gene: LTBP2 was added
gene: LTBP2 was added to Ehlers Danlos syndromes. Sources: Literature
Mode of inheritance for gene: LTBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP2 were set to PMID: 20179738; PMID: 20617341
Phenotypes for gene: LTBP2 were set to Inreased arm-span-to-height ratio; Decreased upper-to-lower body ratio; Lens dislocation; Pectus excavatum; Myopia
Penetrance for gene: LTBP2 were set to Complete
Review for gene: LTBP2 was set to AMBER
Added comment: Based on the literature several individuals were suspected of marfan syndrome. Not only due to eye changes, but also due to stature, increased arm span and decreased upper-to-lower body ratio.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.92 KIAA1161 Ivone Leong Publications for gene: KIAA1161 were set to 30656188; 30649222; 30460687; 29910000; 31951047; 33958240, 30649222
White matter disorders and cerebral calcification - childhood onset v1.91 KIAA1161 Ivone Leong Publications for gene: KIAA1161 were set to 30656188; 30649222; 30460687; 29910000; 31951047
White matter disorders and cerebral calcification - childhood onset v1.90 ZFYVE26 Ivone Leong Classified gene: ZFYVE26 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.90 ZFYVE26 Ivone Leong Added comment: Comment on list classification: Promoted Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene is Green on the White matter disorders - adult onset (Version 1.10) panel. The age of onset can be in childhood. This gene should be Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.90 ZFYVE26 Ivone Leong Gene: zfyve26 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.89 ZFYVE26 Ivone Leong Tag Q2_21_rating tag was added to gene: ZFYVE26.
White matter disorders and cerebral calcification - childhood onset v1.89 KIAA1161 Ivone Leong Phenotypes for gene: KIAA1161 were changed from to Basal ganglia calcification, idiopathic, 7, autosomal recessive, OMIM:618317
White matter disorders and cerebral calcification - childhood onset v1.88 KIAA1161 Ivone Leong commented on gene: KIAA1161
White matter disorders and cerebral calcification - childhood onset v1.88 KIAA1161 Ivone Leong Tag new-gene-name tag was added to gene: KIAA1161.
Dilated Cardiomyopathy and conduction defects v1.70 SPEG Ivone Leong Classified gene: SPEG as Green List (high evidence)
Dilated Cardiomyopathy and conduction defects v1.70 SPEG Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my previous review.
Dilated Cardiomyopathy and conduction defects v1.70 SPEG Ivone Leong Gene: speg has been classified as Green List (High Evidence).
Dilated Cardiomyopathy and conduction defects v1.69 SPEG Ivone Leong Tag Q2_21_rating was removed from gene: SPEG.
Dilated and arrhythmogenic cardiomyopathy v1.25 SPEG Ivone Leong Entity copied from Cardiomyopathies - including childhood onset v1.42
Dilated and arrhythmogenic cardiomyopathy v1.25 SPEG Ivone Leong gene: SPEG was added
gene: SPEG was added to Dilated cardiomyopathy - adult and teen. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: SPEG.
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 32925938; 33794647; 33926407
Phenotypes for gene: SPEG were set to Dilated cardiomyopathy, MONDO:0005021; Centronuclear myopathy 5, OMIM:615959
Dilated Cardiomyopathy and conduction defects v1.69 SPEG Ivone Leong Entity copied from Cardiomyopathies - including childhood onset v1.42
Dilated Cardiomyopathy and conduction defects v1.69 SPEG Ivone Leong gene: SPEG was added
gene: SPEG was added to Dilated Cardiomyopathy and conduction defects. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: SPEG.
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 32925938; 33794647; 33926407
Phenotypes for gene: SPEG were set to Dilated cardiomyopathy, MONDO:0005021; Centronuclear myopathy 5, OMIM:615959
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Tag Q2_21_rating tag was added to gene: SPEG.
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Classified gene: SPEG as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. DCM is are reported in some of the reported cases (>3 cases). This gene has enough evidence to support a gene-disease association. This gene should be Green at the next review.
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Gene: speg has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.41 SPEG Ivone Leong Publications for gene: SPEG were set to 32925938; 33794647
Paediatric or syndromic cardiomyopathy v1.40 SPEG Ivone Leong Phenotypes for gene: SPEG were changed from Dilated cardiomyopathy; centronuclear myopathy to Dilated cardiomyopathy, MONDO:0005021; Centronuclear myopathy 5, OMIM:615959
Severe microcephaly v2.150 PPP1R15B Eleanor Williams changed review comment from: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly, but two have the same variant reported.; to: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly (2 severe), but two have the same variant reported.
Severe microcephaly v2.150 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Severe microcephaly v2.150 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Intellectual disability v3.1076 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Intellectual disability v3.1076 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Ataxia and cerebellar anomalies - childhood onset v2.174 MINPP1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MINPP1.
Ataxia and cerebellar anomalies - childhood onset v2.174 MINPP1 Arina Puzriakova Publications for gene: MINPP1 were set to 33257696
Ataxia and cerebellar anomalies - childhood onset v2.173 MINPP1 Arina Puzriakova Classified gene: MINPP1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.173 MINPP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green status at the next GMS panel update.

To date, at least 16 individuals from 10 unrelated families reported, all with different biallelic variants in MINPP1 (5 truncating, 6 missense). Main clinical characteristics included mild to severe PCH on brain MRI (16/16), moderate to severe DD/ID (16/16), microcephaly (14/16), and seizures (12/16). Supported by some functional data (PMIDs: 33257696; 33168985)
Ataxia and cerebellar anomalies - childhood onset v2.173 MINPP1 Arina Puzriakova Gene: minpp1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Tag Q2_21_rating tag was added to gene: CERS1.
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh edited their review of gene: CERS1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two missense variants reported in two unrelated cases, together with supportive functional evidence.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Classified gene: CERS1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.351 CERS1 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 v2.351 CERS1 Sarah Leigh Gene: cers1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.350 CERS1 Sarah Leigh Phenotypes for gene: CERS1 were changed from ?Epilepsy, progressive myoclonic, 8, 616230 to ?Epilepsy, progressive myoclonic, 8 OMIM:616230; progressive myoclonic epilepsy type 8 MONDO:0014545
Early onset or syndromic epilepsy v2.349 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Early onset or syndromic epilepsy v2.348 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Severe microcephaly v2.149 PPP1R15B Eleanor Williams Added comment: Comment on publications: Previous publication entry:
26307080: In a Canadian sister and brother, born of second-cousin parents, with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) identified homozygosity for a c.1972C-T mutation in PPP1R15B (R658C);26159176: In a brother and sister from a consanguineous Algerian family with microcephaly, short stature, intellectual disability, and diabetes (MSSGM2, 616817), Abdulkarim et al. (2015) identified homozygosity for the R658C substitution.
Severe microcephaly v2.149 PPP1R15B Eleanor Williams Publications for gene: PPP1R15B were set to 26307080: In a Canadian sister and brother, born of second-cousin parents, with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) identified homozygosity for a c.1972C-T mutation in PPP1R15B (R658C); 26159176: In a brother and sister from a consanguineous Algerian family with microcephaly, short stature, intellectual disability, and diabetes (MSSGM2, 616817), Abdulkarim et al. (2015) identified homozygosity for the R658C substitution.
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Classified gene: PPP1R15B as Amber List (moderate evidence)
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly, but two have the same variant reported.
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Gene: ppp1r15b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.147 PPP1R15B Eleanor Williams changed review comment from: Associated with Microcephaly, short stature, and impaired glucose metabolism 2 #616817 in OMIM.

PubMed: 27640355 - Mohammad et al 2016 - report WES of 2 siblings who presented with cirrhosis and required liver transplantation at age 7 and 22 months. Compound heterozygous mutations in PPP1R15B were identified. Microcephaly was also noted in both siblings. One sibling at age 4 years had head circumference at the third percentile, the other had holoprosencephaly and head circumference was below the 3rd percentile for gestational age at birth. Compound het variants in PPP1R15B; c.63G>A (p.W21*), inherited from the father, and c.674delC (p.P225LfsX10), inherited from the mother.

PubMed: 26159176 - Abdulkarim et al 2015 - report a homozygous c.1972C>T, p.R658C variant in PPP1R15B in two siblings from a consanguineous family of Algerian origin with young-onset diabetes, microcephaly, and short stature. First sibling had adult cranial perimeter: 46 cm, −4.0 SD. The sister had a similar presentation but was not available for detailed evaluation.

PubMed: 26307080 - Kernohan et al 2015 - report a consanguineous family (ethnicity not stated) with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings and a homozygous c.1972G>A; p.R658C variant in PPP1R15B. First sibling had head circumference of 28.5 cm (−5.0 SD) at birth, second sibling had a head circumference of head circumference of 37 cm (−6 to −7 SD) at 15 months.; to: Associated with Microcephaly, short stature, and impaired glucose metabolism 2 #616817 in OMIM.

PubMed: 27640355 - Mohammad et al 2016 - report WES of 2 siblings who presented with cirrhosis and required liver transplantation at age 7 and 22 months. Compound heterozygous mutations in PPP1R15B were identified. Microcephaly was also noted in both siblings. One sibling at age 4 years had head circumference at the third percentile, the other had holoprosencephaly and head circumference was below the 3rd percentile for gestational age at birth. Compound het variants in PPP1R15B; c.63G>A (p.W21*), inherited from the father, and c.674delC (p.P225LfsX10), inherited from the mother.

PubMed: 26159176 - Abdulkarim et al 2015 - report a homozygous c.1972C>T, p.R658C variant in PPP1R15B in two siblings from a consanguineous family of Algerian origin with young-onset diabetes, microcephaly, and short stature. First sibling had adult cranial perimeter: 46 cm, −4.0 SD. The sister had a similar presentation but was not available for detailed evaluation.

PubMed: 26307080 - Kernohan et al 2015 - report a consanguineous family (enrolled in Canada) with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings and a homozygous c.1972G>A; p.R658C variant in PPP1R15B. First sibling had head circumference of 28.5 cm (−5.0 SD) at birth, second sibling had a head circumference of head circumference of 37 cm (−6 to −7 SD) at 15 months.
Severe microcephaly v2.147 PPP1R15B Eleanor Williams Phenotypes for gene: PPP1R15B were changed from Microcephaly, short stature, and impaired glucose metabolism 2, 616817; MSSGM2 to Microcephaly, short stature, and impaired glucose metabolism 2, OMIM:616817
Severe microcephaly v2.146 PPP1R15B Eleanor Williams reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27640355, 26159176, 26307080; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, OMIM:616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.347 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Classified gene: NSF as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Gene: nsf has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1075 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.345 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.172 PMPCB Sarah Leigh Tag Q2_21_rating tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Tag Q2_21_rating tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh edited their review of gene: PMPCB: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.172 PMPCB Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).
Ataxia and cerebellar anomalies - childhood onset v2.172 PMPCB Sarah Leigh edited their review of gene: PMPCB: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Classified gene: PMPCB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.345 PMPCB 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 v2.345 PMPCB Sarah Leigh Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.172 PMPCB Sarah Leigh Classified gene: PMPCB as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.172 PMPCB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.172 PMPCB Sarah Leigh Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.48 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Mitochondrial disorders v2.35 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Intellectual disability v3.1075 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Early onset or syndromic epilepsy v2.344 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Likely inborn error of metabolism v2.134 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Possible mitochondrial disorder, nuclear genes v1.42 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Ataxia and cerebellar anomalies - childhood onset v2.171 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Dystonia, chorea or related movement disorder, childhood onset v1.103 GLRB Sarah Leigh Tag Q2_21_rating tag was added to gene: GLRB.
Dystonia, chorea or related movement disorder, childhood onset v1.103 GLRB Sarah Leigh edited their review of gene: GLRB: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least four variants reported in three unrelated cases.; Changed rating: GREEN
Dystonia, chorea or related movement disorder, childhood onset v1.103 GLRB Sarah Leigh Classified gene: GLRB as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.103 GLRB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.103 GLRB Sarah Leigh Gene: glrb has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.47 GLRB Sarah Leigh Publications for gene: GLRB were set to 23238346; 11929858; 21391991
White matter disorders and cerebral calcification - childhood onset v1.88 ERCC5 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC5.
White matter disorders and cerebral calcification - childhood onset v1.88 ERCC5 Eleanor Williams Classified gene: ERCC5 as Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.88 ERCC5 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green but with a recommendation for amber or red rating following GMS review. As Expert reviewer reports there is no specific white matter abnormalities/leukodystrphy reported in the cases to date.
White matter disorders and cerebral calcification - childhood onset v1.88 ERCC5 Eleanor Williams Gene: ercc5 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.87 ERCC5 Eleanor Williams Phenotypes for gene: ERCC5 were changed from Xeroderma pigmentosum, group G, 278780; Xeroderma pigmentosum, group G/Cockayne syndrome, 278780 to Cerebrooculofacioskeletal syndrome 3 OMIM:616570; Xeroderma pigmentosum, group G/Cockayne syndrome OMIM:278780
White matter disorders and cerebral calcification - childhood onset v1.86 ERCC5 Eleanor Williams Publications for gene: ERCC5 were set to
White matter disorders and cerebral calcification - childhood onset v1.85 ERCC5 Eleanor Williams reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 8818951, 9096355, 24700531, 11228268, 8317483; Phenotypes: Cerebrooculofacioskeletal syndrome 3 OMIM:616570, Xeroderma pigmentosum, group G/Cockayne syndrome OMIM:278780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.46 GLRB Sarah Leigh Phenotypes for gene: GLRB were changed from Hyperekplexia 2, 614619 to Hyperekplexia 2 OMIM:614619; hyperekplexia 2 MONDO:0013828
Paroxysmal central nervous system disorders v1.12 GLRB Sarah Leigh Phenotypes for gene: GLRB were changed from Hyperekplexia 2, 614619 to Hyperekplexia 2 OMIM:614619; hyperekplexia 2 MONDO:0013828
Paroxysmal central nervous system disorders v1.11 GLRB Sarah Leigh Publications for gene: GLRB were set to 23238346; 11929858; 21391991
Dystonia, chorea or related movement disorder, childhood onset v1.102 GLRB Sarah Leigh Publications for gene: GLRB were set to 21391991; 23238346; 11929858
Dystonia, chorea or related movement disorder, childhood onset v1.101 GLRB Sarah Leigh Phenotypes for gene: GLRB were changed from Hyperekplexia 2, 614619 to Hyperekplexia 2 OMIM:614619; hyperekplexia 2 MONDO:0013828
Likely inborn error of metabolism v2.133 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Intellectual disability v3.1074 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Ataxia and cerebellar anomalies - childhood onset v2.170 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hypertrophic cardiomyopathy v2.21 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary ataxia v1.221 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Ataxia and cerebellar anomalies - childhood onset v2.169 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary ataxia, adult onset v2.45 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreichataxia, 229300; Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes,229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Likely inborn error of metabolism v2.132 FXN Sarah Leigh Added comment: Comment on phenotypes: Friedreich ataxia, 229300;Friedreich ataxia with retained reflexes, 229300;Hereditary ataxia;Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Likely inborn error of metabolism v2.132 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300; Hereditary ataxia; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary neuropathy v1.385 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Hereditary Neuropathies; Friedreich ataxia, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary spastic paraplegia, adult onset v1.20 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary spastic paraplegia, childhood onset v2.33 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary ataxia v1.220 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreichataxia,229300Friedreichataxiawithretainedreflexes,229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Ataxia and cerebellar anomalies - childhood onset v2.168 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreichataxia,229300Friedreichataxiawithretainedreflexes,229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
White matter disorders and cerebral calcification - childhood onset v1.85 ERCC4 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC4.
White matter disorders and cerebral calcification - childhood onset v1.85 ERCC4 Eleanor Williams Phenotypes for gene: ERCC4 were changed from Xeroderma pigmentosum, type F/Cockayne syndrome, 278760; Xeroderma pigmentosum, group F, 278760 to Xeroderma pigmentosum, type F/Cockayne syndrome, OMIM:278760; XFE progeroid syndrome, OMIM:610965
White matter disorders and cerebral calcification - childhood onset v1.84 ERCC4 Eleanor Williams Publications for gene: ERCC4 were set to
White matter disorders and cerebral calcification - childhood onset v1.83 ERCC4 Eleanor Williams Classified gene: ERCC4 as Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.83 ERCC4 Eleanor Williams Added comment: Comment on list classification: Leaving as green for now, but with a recommendation for an amber rating following GMS review. One case where white matter lesions are reported as part of a broader phenotype and 2 cases with milder phenotypes related to white matter.
White matter disorders and cerebral calcification - childhood onset v1.83 ERCC4 Eleanor Williams Gene: ercc4 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.167 CAD Arina Puzriakova Publications for gene: CAD were set to 32820246
Ataxia and cerebellar anomalies - childhood onset v2.166 CAD Arina Puzriakova Classified gene: CAD as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.166 CAD Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There are sufficient cases with ataxia and biallelic variants in this gene to rate as Green on this panel, but note that not all cases present this feature (ataxia reported in 8/18 individuals to date - PMID: 32820246)
Ataxia and cerebellar anomalies - childhood onset v2.166 CAD Arina Puzriakova Gene: cad has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.82 ERCC4 Eleanor Williams reviewed gene: ERCC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 23623389, 29105242; Phenotypes: Xeroderma pigmentosum, type F/Cockayne syndrome, OMIM:278760, XFE progeroid syndrome, OMIM:610965; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.165 CAD Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAD.
White matter disorders and cerebral calcification - childhood onset v1.82 ERCC3 Eleanor Williams Phenotypes for gene: ERCC3 were changed from Xeroderma pigmentosum, group B, 610651; Trichothiodystrophy, 601675 to Trichothiodystrophy 2, photosensitive, OMIM:616390; Xeroderma pigmentosum, group B, OMIM:610651
White matter disorders and cerebral calcification - childhood onset v1.81 ERCC3 Eleanor Williams Publications for gene: ERCC3 were set to
White matter disorders and cerebral calcification - childhood onset v1.80 ERCC3 Eleanor Williams Classified gene: ERCC3 as Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.80 ERCC3 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green, but with recommendation for red rating following GMS review. No evidence that variants in this gene is associated with white matter disease.
White matter disorders and cerebral calcification - childhood onset v1.80 ERCC3 Eleanor Williams Gene: ercc3 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.79 ERCC3 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC3.
White matter disorders and cerebral calcification - childhood onset v1.79 ERCC3 Eleanor Williams reviewed gene: ERCC3: Rating: RED; Mode of pathogenicity: None; Publications: 9012405, 2167179, 16947863, 8408834, 8304337; Phenotypes: Trichothiodystrophy 2, photosensitive, OMIM:616390, Xeroderma pigmentosum, group B, OMIM:610651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.165 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50; OMIM # 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Early onset or syndromic epilepsy v2.343 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Intellectual disability v3.1073 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Tag Q2_21_rating tag was added to gene: TMEM222.
Intellectual disability v3.1072 TMEM222 Sarah Leigh Tag Q2_21_rating tag was added to gene: TMEM222.
Intellectual disability v3.1072 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Moderate to severe intellectual disability was evident in all families.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Seizures were evident in six individuals from six families.; Changed rating: GREEN
Intellectual disability v3.1072 TMEM222 Sarah Leigh Classified gene: TMEM222 as Amber List (moderate evidence)
Intellectual disability v3.1072 TMEM222 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 v3.1072 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Classified gene: TMEM222 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.342 TMEM222 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 v2.342 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.341 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Intellectual disability v3.1071 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Pulmonary arterial hypertension v2.13 KDR Stefan Graf reviewed gene: KDR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33320693, 31980491; Phenotypes: pulmonary arterial hypertension, significantly reduced diffusing coefficient for carbon monoxide, late disease onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Parkinson Disease and Complex Parkinsonism v1.70 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from ?{Parkinson disease 5, susceptibility to} to {?Parkinson disease 5, susceptibility to}, OMIM:613643
Hereditary spastic paraplegia, adult onset v1.19 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491, AR to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Hereditary spastic paraplegia, adult onset v1.18 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to 29735986; 28007905; 23359680
Hereditary spastic paraplegia, adult onset v1.17 UCHL1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: UCHL1.
Hereditary spastic paraplegia, adult onset v1.17 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.44 UCHL1 Arina Puzriakova changed review comment from: Tagged for GMS expert review (Q2_21) to seek opinion on whether this gene rating needs to be changed. Ten individuals from four families have been reported with a childhood-onset neurodegenerative disorder and different biallelic variants in this gene. Age of onset ranges from 2 to 10 years, however visual loss appears to be one of the first presenting features in most cases and ataxia becomes apparent later in the clinical course (PMIDs: 23359680; 28007905; 29735986; 32656641); to: Tagged for GMS expert review (Q2_21) to seek opinion on whether this gene rating needs to be changed. Ten individuals from four families have been reported with a childhood-onset neurodegenerative disorder and different biallelic variants in this gene. Age of onset ranges from 2 to 10 years, however visual loss appears to be one of the first presenting features in most cases and ataxia becomes apparent later in the clinical course (PMIDs: 23359680; 28007905; 29735986; 32656641). Inclusion may be justified to ensure that edge cases may be identified.
Hereditary spastic paraplegia, childhood onset v2.32 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491, AR to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Hereditary spastic paraplegia, childhood onset v2.31 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to 29735986; 28007905; 23359680
Hereditary ataxia, adult onset v2.44 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy; Autosomal recessive spastic paraplegia 79, 615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Hereditary ataxia, adult onset v2.43 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to 23359680
Hereditary ataxia, adult onset v2.42 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.42 UCHL1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: UCHL1.
Hereditary ataxia v1.219 UCHL1 Arina Puzriakova Classified gene: UCHL1 as Green List (high evidence)
Hereditary ataxia v1.219 UCHL1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with different biallelic variants, supported by functional and animal model data.
Hereditary ataxia v1.219 UCHL1 Arina Puzriakova Gene: uchl1 has been classified as Green List (High Evidence).
Hereditary ataxia v1.218 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Hereditary ataxia v1.217 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to PMID: 23359680
Hereditary ataxia v1.216 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641, 11555633, 33159930; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.164 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Ataxia and cerebellar anomalies - childhood onset v2.163 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to PMID: 23359680
Ataxia and cerebellar anomalies - childhood onset v2.162 UCHL1 Arina Puzriakova Classified gene: UCHL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.162 UCHL1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with biallelic variants, supported by functional and animal model data.
Ataxia and cerebellar anomalies - childhood onset v2.162 UCHL1 Arina Puzriakova Gene: uchl1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.161 UCHL1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UCHL1.
Ataxia and cerebellar anomalies - childhood onset v2.161 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641, 11555633, 33159930; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1070 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Intellectual disability v3.1070 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Intellectual disability. Sources: Literature,Expert Review Red
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Familial pulmonary fibrosis v1.16 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Familial pulmonary fibrosis v1.16 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Familial pulmonary fibrosis. Sources: Expert Review Red,Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Intracerebral calcification disorders v1.28 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Intracerebral calcification disorders v1.28 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Intracerebral calcification disorders. Sources: Expert Review Red,Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Cholestasis v1.84 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Cholestasis v1.84 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Cholestasis. Sources: Expert Review Red,Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
White matter disorders and cerebral calcification - childhood onset v1.79 FARSA Ivone Leong Classified gene: FARSA as Red List (low evidence)
White matter disorders and cerebral calcification - childhood onset v1.79 FARSA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
White matter disorders and cerebral calcification - childhood onset v1.79 FARSA Ivone Leong Gene: farsa has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.78 FARSA Ivone Leong Phenotypes for gene: FARSA were changed from Rajab interstitial lung disease with brain calcifications 2, OMIM:619013 to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
White matter disorders and cerebral calcification - childhood onset v1.77 FARSA Ivone Leong Phenotypes for gene: FARSA were changed from Rajab interstitial lung disease with brain calcifications 2, MIM# 619013 to Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
White matter disorders and cerebral calcification - childhood onset v1.76 ZFYVE26 Ivone Leong Phenotypes for gene: ZFYVE26 were changed from Spastic paraplegia 15, autosomal recessive, MIM#270700 to Spastic paraplegia 15, autosomal recessive, OMIM:270700
White matter disorders and cerebral calcification - childhood onset v1.75 ZFYVE26 Ivone Leong Publications for gene: ZFYVE26 were set to
White matter disorders and cerebral calcification - childhood onset v1.74 WARS2 Ivone Leong Tag Q2_21_rating tag was added to gene: WARS2.
White matter disorders and cerebral calcification - childhood onset v1.74 WARS2 Ivone Leong Classified gene: WARS2 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.74 WARS2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.74 WARS2 Ivone Leong Gene: wars2 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.73 WARS2 Ivone Leong Phenotypes for gene: WARS2 were changed from Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, MIM# 617710 to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, OMIM:617710
Severe insulin resistance and lipodystrophy syndromes v2.15 OTULIN Ivone Leong Classified gene: OTULIN as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v2.15 OTULIN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe insulin resistance and lipodystrophy syndromes v2.15 OTULIN Ivone Leong Gene: otulin has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v2.14 OTULIN Ivone Leong Tag Q2_21_rating tag was added to gene: OTULIN.
Severe insulin resistance and lipodystrophy syndromes v2.14 KCNJ6 Ivone Leong Classified gene: KCNJ6 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v2.14 KCNJ6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe insulin resistance and lipodystrophy syndromes v2.14 KCNJ6 Ivone Leong Gene: kcnj6 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v2.13 KCNJ6 Ivone Leong Tag Q2_21_rating tag was added to gene: KCNJ6.
Severe insulin resistance and lipodystrophy syndromes v2.13 FBN1 Ivone Leong Classified gene: FBN1 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v2.13 FBN1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe insulin resistance and lipodystrophy syndromes v2.13 FBN1 Ivone Leong Gene: fbn1 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v2.12 FBN1 Ivone Leong Tag Q2_21_rating tag was added to gene: FBN1.
Intellectual disability v3.1069 CAPN15 Zornitza Stark gene: CAPN15 was added
gene: CAPN15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 33410501; 32885237
Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318
Review for gene: CAPN15 was set to GREEN
gene: CAPN15 was marked as current diagnostic
Added comment: 5 families reported, including DD/ID in 3. Profound in one family with bi-allelic LoF variant, PMID 33410501.
Sources: Literature
Intellectual disability v3.1069 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
gene: CHD5 was marked as current diagnostic
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Intellectual disability v3.1069 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP, including ID.

AR ID: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.; Changed rating: GREEN; Changed publications to: 24623383, 33675180, 32989326
Paediatric or syndromic cardiomyopathy v1.39 SPEG Zornitza Stark gene: SPEG was added
gene: SPEG was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 32925938; 33794647
Phenotypes for gene: SPEG were set to Dilated cardiomyopathy; centronuclear myopathy
Review for gene: SPEG was set to GREEN
Added comment: Reports of early onset isolated DCM, as well as cardiomyopathy in the context of skeletal myopathy.
Sources: Literature
Proteinuric renal disease v2.50 RCAN1 Zornitza Stark gene: RCAN1 was added
gene: RCAN1 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: RCAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RCAN1 were set to 33863784
Phenotypes for gene: RCAN1 were set to FSGS; proteinuria
Review for gene: RCAN1 was set to AMBER
Added comment: Two families reported, some functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 ZNFX1 Zornitza Stark reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33872655, 33876776; Phenotypes: Multisystem inflammation, susceptibility to viral infections; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 STXBP3 Zornitza Stark reviewed gene: STXBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33891011; Phenotypes: Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss, Immune Dysregulation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Skeletal dysplasia v2.97 NEPRO Zornitza Stark gene: NEPRO was added
gene: NEPRO was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853
Review for gene: NEPRO was set to AMBER
Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant. PMID 31250547: 1 family with homozygous novel missense All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.72 LSM7 Zornitza Stark gene: LSM7 was added
gene: LSM7 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to https://doi.org/10.1016/j.xhgg.2021.100034
Phenotypes for gene: LSM7 were set to Leukodystrophy; fetal death
Review for gene: LSM7 was set to RED
Added comment: Homozygous variant (p.Asp41Asn) identified in a child with leukodystrophy and a homozygous variant (p.Arg69Pro) identified in an individual that died in utero. In vitro and in vivo (zebrafish) assays supporting pathogenicity of the 2 variants.
Sources: Literature
Intellectual disability v3.1069 PTPN4 Zornitza Stark gene: PTPN4 was added
gene: PTPN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability
Review for gene: PTPN4 was set to GREEN
gene: PTPN4 was marked as current diagnostic
Added comment: >3 unrelated probands and supportive mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.72 POLR3K Zornitza Stark gene: POLR3K was added
gene: POLR3K was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310
Review for gene: POLR3K was set to AMBER
Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes.

Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Literature
Congenital muscular dystrophy v2.8 JAG2 Zornitza Stark gene: JAG2 was added
gene: JAG2 was added to Congenital muscular dystrophy. Sources: Literature
Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAG2 were set to 33861953
Phenotypes for gene: JAG2 were set to muscular dystrophy
Review for gene: JAG2 was set to GREEN
gene: JAG2 was marked as current diagnostic
Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy.
Sources: Literature
Intellectual disability v3.1069 ANKRD17 Zornitza Stark gene: ANKRD17 was added
gene: ANKRD17 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKRD17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD17 were set to 33909992
Phenotypes for gene: ANKRD17 were set to Intellectual disability, speech delay, and dysmorphism
Review for gene: ANKRD17 was set to GREEN
gene: ANKRD17 was marked as current diagnostic
Added comment: 34 predominantly LoF variants reported - 29 de novo, 1 inherited from an affected parent, 1 inherited from a suspected mosaic parent. Main phenotypes were dev delay/ID, motor delay, and speech delay.
Sources: Literature
Intellectual disability v3.1069 SIN3B Zornitza Stark gene: SIN3B was added
gene: SIN3B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIN3B were set to 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability
Review for gene: SIN3B was set to GREEN
gene: SIN3B was marked as current diagnostic
Added comment: PMID: 33811806
- 9 affected individuals, variants all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
Sources: Literature
Intellectual disability v3.1069 DPYSL5 Zornitza Stark gene: DPYSL5 was added
gene: DPYSL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
gene: DPYSL5 was marked as current diagnostic
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.100 VPS41 Zornitza Stark edited their review of gene: VPS41: Added comment: PMID 33764426: Additional 9 individuals from 5 unrelated families reported.; Changed rating: GREEN; Changed publications to: 32808683, 33764426; Set current diagnostic: yes
Renal ciliopathies v1.41 XPNPEP3 Zornitza Stark reviewed gene: XPNPEP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32660933, 20179356; Phenotypes: Nephronophthisis-like nephropathy 1, OMIM #613159; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ehlers Danlos syndrome with a likely monogenic cause v2.57 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Set current diagnostic: yes
Ehlers Danlos syndrome with a likely monogenic cause v2.57 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Added comment: PMID 33807164: third unrelated family reported, single affected individual with bi-alllelic LoF variant, cutis laxa and multiple herniations.; Changed rating: GREEN; Changed publications to: 32006683, 31792352, 33807164
White matter disorders and cerebral calcification - childhood onset v1.72 LIG3 Zornitza Stark gene: LIG3 was added
gene: LIG3 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy
Review for gene: LIG3 was set to GREEN
Added comment: Seven individuals from three unrelated families and functional data, variable ages of onset from early childhood to late adolescence.
Sources: Literature
Proteinuric renal disease v2.50 PRDM15 Zornitza Stark gene: PRDM15 was added
gene: PRDM15 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM15 were set to 31950080
Phenotypes for gene: PRDM15 were set to Steroid resistant nephrotic syndrome; Holoprosencephaly
Review for gene: PRDM15 was set to AMBER
Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic SRNS including HPE, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data focused on the brain phenotype. Two additional homozygous missense identified with isolated SRNS.
Sources: Literature
Rare anaemia v1.21 SLC19A1 Zornitza Stark gene: SLC19A1 was added
gene: SLC19A1 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275
Phenotypes for gene: SLC19A1 were set to Megaloblastic anemia, folate-responsive, MIM# 601775
Review for gene: SLC19A1 was set to RED
Added comment: Single individual reported with in-frame deletion, some functional data.
Sources: Literature
Monogenic hearing loss v2.162 GREB1L Zornitza Stark gene: GREB1L was added
gene: GREB1L was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to 29955957; 32585897
Phenotypes for gene: GREB1L were set to Deafness, autosomal dominant 80, MIM# 619274
Review for gene: GREB1L was set to GREEN
gene: GREB1L was marked as current diagnostic
Added comment: DFNA80 is characterized by nonsyndromic congenital deafness associated with absent or malformed cochleae and eighth cranial nerves.

Four unrelated families reported, no comment on a renal phenotype. Note variants in this gene are also associated with renal agenesis.
Sources: Literature
Intellectual disability v3.1069 EMC10 Zornitza Stark edited their review of gene: EMC10: Added comment: PMID 33531666: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
Early onset or syndromic epilepsy v2.340 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to AMBER
Added comment: Seizures have been reported in 7 individuals (from 6 families). Consider inclusion with amber/green rating. From the ID panel :

Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Intellectual disability v3.1069 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Fetal anomalies v1.649 CLTC Arina Puzriakova Publications for gene: CLTC were set to
Intellectual disability v3.1069 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability, Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Early onset or syndromic epilepsy v2.340 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability; Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SASH3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Classified gene: SASH3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals presenting combined immunodeficiency in association with variants in this gene. Supported by functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Gene: sash3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.648 RFWD3 Rhiannon Mellis gene: RFWD3 was added
gene: RFWD3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RFWD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFWD3 were set to PMID: 2869192
Phenotypes for gene: RFWD3 were set to Fanconi anaemia
Review for gene: RFWD3 was set to RED
Added comment: Fetally relevant phenotype but only one case reported in literature so far so await further cases.

(In the single reported case, the child had: intrauterine growth retardation, duodenal atresia, radial ray malformations, bilateral absent thumbs, small midface, ventriculomegaly, hypoplastic left kidney, and polysplenia. Brain MRI showed rarefied periventricular white matter, narrow corpus callosum, abnormal pituitary, and Chiari malformation type I)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.420 SASH3 Arina Puzriakova Publications for gene: SASH3 were set to
White matter disorders and cerebral calcification - childhood onset v1.72 ERCC2 Eleanor Williams Classified gene: ERCC2 as Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.72 ERCC2 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green, but with a recommendation of an amber rating following GMS review. Only one case reported with a white matter abnormality.
White matter disorders and cerebral calcification - childhood onset v1.72 ERCC2 Eleanor Williams Gene: ercc2 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.71 ERCC2 Eleanor Williams Phenotypes for gene: ERCC2 were changed from Xeroderma pigmentosum, group D, 278730; Trichothiodystrophy, 601675 to Trichothiodystrophy 1, photosensitive, OMIM:601675
White matter disorders and cerebral calcification - childhood onset v1.70 ERCC2 Eleanor Williams Publications for gene: ERCC2 were set to MIM#601675
White matter disorders and cerebral calcification - childhood onset v1.69 ERCC2 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC2.
White matter disorders and cerebral calcification - childhood onset v1.69 ERCC2 Eleanor Williams commented on gene: ERCC2
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 SPI1 Boaz Palterer gene: SPI1 was added
gene: SPI1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPI1 were set to 33951726
Phenotypes for gene: SPI1 were set to agammaglobulinemia
Penetrance for gene: SPI1 were set to unknown
Review for gene: SPI1 was set to GREEN
Added comment: Carole le Coz et al. described 6 unrelated patients with agammaglobulinemia harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1.
The phenotype was functionally replicated by transfection of mutant PU.1
(https://rupress.org/jem/article-abstract/218/7/e20201750/212070/Constrained-chromatin-accessibility-in-PU-1?redirectedFrom=fulltext)
Sources: Literature
Intellectual disability v3.1068 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1067 UBTF Arina Puzriakova Publications for gene: UBTF were set to 26350204; 28777933
Dystonia, chorea or related movement disorder, childhood onset v1.100 UBTF Arina Puzriakova Classified gene: UBTF as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.100 UBTF Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green status at the next GMS panel update
Dystonia, chorea or related movement disorder, childhood onset v1.100 UBTF Arina Puzriakova Gene: ubtf has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.99 UBTF Arina Puzriakova Publications for gene: UBTF were set to 28777933; 29300972
Dystonia, chorea or related movement disorder, childhood onset v1.98 UBTF Arina Puzriakova Tag Q2_21_rating tag was added to gene: UBTF.
Dystonia, chorea or related movement disorder, childhood onset v1.98 UBTF Arina Puzriakova edited their review of gene: UBTF: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Dystonia, chorea or related movement disorder, childhood onset v1.98 UBTF Arina Puzriakova reviewed gene: UBTF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777933, 29300972, 30517966, 31931739, 33026538; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v2.161 UBTF Arina Puzriakova Publications for gene: UBTF were set to 29300972
Ataxia and cerebellar anomalies - childhood onset v2.160 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF 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
Ataxia and cerebellar anomalies - childhood onset v2.159 UBTF Arina Puzriakova Classified gene: UBTF as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.159 UBTF Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 9 unrelated individuals from different ethnic backgrounds in literature with neuroregression including ataxia as an early feature due to a recurrent variant in this gene (PMIDs: 28777933; 29300972; 30517966; 31931739)
Ataxia and cerebellar anomalies - childhood onset v2.159 UBTF Arina Puzriakova Gene: ubtf has been classified as Amber List (Moderate Evidence).
Inherited white matter disorders v1.94 VPS11 Ivone Leong Classified gene: VPS11 as Green List (high evidence)
Inherited white matter disorders v1.94 VPS11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. This gene is also rated Green on the Genetic epilepsy syndromes (Version 2.339).

It is also on the White matter disorders and cerebral calcification - narrow panel (Version 1.69) as an Amber gene with a recommendation to be promoted to Green. The following review is present:

"Recurrent homozygous variant, p.Cys846Gly identified in more than 10 families of Ashkenazi Jewish descent. One other variant reported in another family in PMID 27473128. Functional data.
Zornitza Stark (Australian Genomics), 16 Sep 2020"

There is enough evidence to support a gene-disease association.
Inherited white matter disorders v1.94 VPS11 Ivone Leong Gene: vps11 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.93 VPS11 Ivone Leong Phenotypes for gene: VPS11 were changed from Leukodystrophy, hypomyelinating, 12, MIM#616683 to Leukodystrophy, hypomyelinating, 12, OMIM:616683
Inherited white matter disorders v1.92 VPS11 Ivone Leong Publications for gene: VPS11 were set to 26307567, 27120463
Ataxia and cerebellar anomalies - childhood onset v2.158 UBTF Arina Puzriakova Tag Q2_21_rating tag was added to gene: UBTF.
Ataxia and cerebellar anomalies - childhood onset v2.158 UBTF Arina Puzriakova reviewed gene: UBTF: 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: 28777933, 29300972, 30517966, 31931739; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1066 VPS11 Ivone Leong commented on gene: VPS11
Intellectual disability v3.1066 VPS11 Ivone Leong Tag watchlist was removed from gene: VPS11.
Tag Q2_21_rating tag was added to gene: VPS11.
White matter disorders and cerebral calcification - childhood onset v1.69 VPS11 Ivone Leong Tag Q2_21_rating tag was added to gene: VPS11.
White matter disorders and cerebral calcification - childhood onset v1.69 VPS11 Ivone Leong Classified gene: VPS11 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.69 VPS11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.69 VPS11 Ivone Leong Gene: vps11 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.68 VPS11 Ivone Leong Phenotypes for gene: VPS11 were changed from Leukodystrophy, hypomyelinating, 12, MIM#616683 to Leukodystrophy, hypomyelinating, 12, OMIM:616683
White matter disorders and cerebral calcification - childhood onset v1.67 VPS11 Ivone Leong Publications for gene: VPS11 were set to 26307567, 27120463
White matter disorders and cerebral calcification - childhood onset v1.66 UFM1 Ivone Leong Tag Q2_21_rating tag was added to gene: UFM1.
White matter disorders and cerebral calcification - childhood onset v1.66 UFM1 Ivone Leong Classified gene: UFM1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.66 UFM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.66 UFM1 Ivone Leong Gene: ufm1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.65 UFM1 Ivone Leong Phenotypes for gene: UFM1 were changed from Leukodystrophy, hypomyelinating, 14, MIM# 617899 to Leukodystrophy, hypomyelinating, 14, OMIM:617899
White matter disorders and cerebral calcification - childhood onset v1.64 TUFM Ivone Leong commented on gene: TUFM: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.64 TUFM Ivone Leong Tag Q2_21_rating tag was added to gene: TUFM.
White matter disorders and cerebral calcification - childhood onset v1.64 TUFM Ivone Leong Phenotypes for gene: TUFM were changed from Mitochondrial Leukoencephalopathy to Mitochondrial Leukoencephalopathy; Combined oxidative phosphorylation deficiency 4, OMIM:610678
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 CHD7 Helen Lord gene: CHD7 was added
gene: CHD7 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: CHD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD7 were set to 33844462; 30498854; 33288889
Phenotypes for gene: CHD7 were set to craniosynostosis
Review for gene: CHD7 was set to AMBER
Added comment: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
White matter disorders and cerebral calcification - childhood onset v1.63 TUFM Ivone Leong Added comment: Comment on publications: 25735936 - summarises the findings of exome analysis in 109 patients. 16 out of 42 patients with a high suspicion of a mitochondrial disorder were reported as having a disease causing mutation found in the mitochondrial gene panel - of which TUFM was one of the genes with the biochemical diagnosis of combined OXPHOS enzyme deficiency.;25655951;17160893 (case report)
White matter disorders and cerebral calcification - childhood onset v1.63 TUFM Ivone Leong Publications for gene: TUFM were set to 25735936 - summarises the findings of exome analysis in 109 patients. 16 out of 42 patients with a high suspicion of a mitochondrial disorder were reported as having a disease causing mutation found in the mitochondrial gene panel - of which TUFM was one of the genes with the biochemical diagnosis of combined OXPHOS enzyme deficiency.; 25655951; 17160893 (case report)
White matter disorders and cerebral calcification - childhood onset v1.62 TMEM63A Ivone Leong Tag Q2_21_rating tag was added to gene: TMEM63A.
White matter disorders and cerebral calcification - childhood onset v1.62 TMEM63A Ivone Leong Publications for gene: TMEM63A were set to 31587869
White matter disorders and cerebral calcification - childhood onset v1.61 TMEM63A Ivone Leong Classified gene: TMEM63A as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.61 TMEM63A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 33597727. 2 additional cases.

PMID: 33785861. 1 additional case.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.61 TMEM63A Ivone Leong Gene: tmem63a has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.61 TMEM63A Ivone Leong Classified gene: TMEM63A as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.61 TMEM63A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 33597727. 2 additional cases.

PMID: 33785861. 1 additional case.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.61 TMEM63A Ivone Leong Gene: tmem63a has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.98 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia; Friedreich ataxia with retained reflexes, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
White matter disorders and cerebral calcification - childhood onset v1.60 TMEM63A Ivone Leong Phenotypes for gene: TMEM63A were changed from Leukodystrophy, hypomyelinating, 19, transient infantile, MIM# 618688 to Leukodystrophy, hypomyelinating, 19, transient infantile, OMIM:618688
Paediatric disorders - additional genes v1.93 CTU2 Ivone Leong Entity copied from Severe microcephaly v2.146
Paediatric disorders - additional genes v1.93 CTU2 Ivone Leong gene: CTU2 was added
gene: CTU2 was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: CTU2.
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546; 27480277; 31301155
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Differences in sex development v2.47 CTU2 Ivone Leong Entity copied from Severe microcephaly v2.146
Differences in sex development v2.47 CTU2 Ivone Leong gene: CTU2 was added
gene: CTU2 was added to Disorders of sex development. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: CTU2.
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546; 27480277; 31301155
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Intellectual disability v3.1066 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from developmental regression; motor and language regression; developmental delay; Neurodegeneration, childhood-onset, with brain atrophy, 617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Ataxia and cerebellar anomalies - childhood onset v2.158 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy MIM#617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Dystonia, chorea or related movement disorder, childhood onset v1.97 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy MIM#617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Intellectual disability v3.1065 DYNC1I2 Arina Puzriakova Phenotypes for gene: DYNC1I2 were changed from Abnormality of nervous system morphology; Abnormality of head or neck; Microcephaly; Intellectual disability to Neurodevelopmental disorder with microcephaly and structural brain anomalies, OMIM:618492
Severe microcephaly v2.146 CTU2 Ivone Leong Tag Q2_21_rating tag was added to gene: CTU2.
Severe microcephaly v2.146 CTU2 Ivone Leong Classified gene: CTU2 as Amber List (moderate evidence)
Severe microcephaly v2.146 CTU2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID:26633546. Affected members of all 3 families have microcephaly, facial dysmorphia and unilateral renal agenesis. 2/3 families have ambiguous genitalia; however, only 1 family had karyotyping done, which showed normal male karyotype (46 XY). 2/3 had congenital heart disease.

PMID: 27480277. Same variant as PMID:26633546. Affected individuals in this extended family have similar phenotype as PMID:26633546. Patient 1: in addition to microcephaly also has renal anomalies (small kidneys) and possible ambiguous genitalia with normal XY karyotype. Patient 2: cousin of patient 1. In addition to microcephaly did not have renal anomalies and nor ambiguous genitalia. Both patients have congenital heart disease.

PMID: 31301155. 5 new cases, all with microcephaly. 4/5 with renal anomalies, 2/5 with ambiguous genitalia, 4/5 congenital heart disease.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.146 CTU2 Ivone Leong Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.145 DYNC1I2 Arina Puzriakova Phenotypes for gene: DYNC1I2 were changed from Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492 to Neurodevelopmental disorder with microcephaly and structural brain anomalies, OMIM:618492
Cerebral vascular malformations v2.51 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from Seckel syndrome 8 615807 to Seckel syndrome 8, OMIM:615807
Intellectual disability v3.1064 DNA2 Arina Puzriakova reviewed gene: DNA2: Rating: RED; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, OMIM:615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.144 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 24389050; 31045292
Intellectual disability v3.1064 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 23352259; 24389050
Intellectual disability v3.1063 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from PRIMORDIAL DWARFISM SECKEL SYNDROME 8; SCKL8 to Seckel syndrome 8, OMIM:615807
Severe microcephaly v2.143 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from Seckel syndrome 8, OMIM:615807 to Seckel syndrome 8, OMIM:615807; Microcephalic primordial dwarfism, MONDO:0017950
Severe microcephaly v2.142 DNA2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DNA2.
Severe microcephaly v2.142 DNA2 Arina Puzriakova Classified gene: DNA2 as Amber List (moderate evidence)
Severe microcephaly v2.142 DNA2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - 4 different homozygous variants identified in at least 5 unrelated families with microcephalic primordial dwarfism (PMIDs: 24389050; 31045292)
Severe microcephaly v2.142 DNA2 Arina Puzriakova Gene: dna2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.131 WFS1 Eleanor Williams Added comment: Comment on phenotypes: Previous phenotypes were: Diabetes with additional phenotypes suggestive of a monogenic aetiology;Inherited optic neuropathies;Wolfram syndrome 1, 222300;Mitochondrial respiratory chain disorders caused by nuclear variants only;Hereditary ataxia;Familial diabetes;Congenital hearing impairment (profound/severe)
Likely inborn error of metabolism v2.131 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Diabetes with additional phenotypes suggestive of a monogenic aetiology; Inherited optic neuropathies; Wolfram syndrome 1, 222300; Mitochondrial respiratory chain disorders caused by nuclear variants only; Hereditary ataxia; Familial diabetes; Congenital hearing impairment (profound/severe) to Wolfram syndrome 1, OMIM:222300; Wolfram-like syndrome, autosomal dominant, OMIM:614296; Diabetes mellitus, noninsulin-dependent, association with, OMIM:125853
Likely inborn error of metabolism v2.130 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27604308; 30171196
Likely inborn error of metabolism v2.129 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.457 WFS1 Eleanor Williams Added comment: Comment on phenotypes: Original phenotypes were: Wolfram syndrome 1 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Congenital hearing impairment (profound/severe); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Familial diabetes; Hereditary ataxia; Inherited optic neuropathies.
Undiagnosed metabolic disorders v1.457 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome 1 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Congenital hearing impairment (profound/severe); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Familial diabetes; Hereditary ataxia; Inherited optic neuropathies to Wolfram syndrome 1, OMIM:222300
Undiagnosed metabolic disorders v1.456 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.157 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome 1, 222300 to Wolfram syndrome 1, OMIM:222300
Ataxia and cerebellar anomalies - childhood onset v2.156 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.141 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 24389050
Severe microcephaly v2.140 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from ?Seckel syndrome 8, 615807; SCKL8 to Seckel syndrome 8, OMIM:615807
Severe microcephaly v2.139 CTU2 Ivone Leong Publications for gene: CTU2 were set to 26633546
Severe microcephaly v2.138 CTU2 Ivone Leong Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MIM#618142) to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Severe microcephaly v2.137 CTCF Ivone Leong Classified gene: CTCF as Amber List (moderate evidence)
Severe microcephaly v2.137 CTCF Ivone Leong Gene: ctcf has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.136 CTCF Ivone Leong gene: CTCF was added
gene: CTCF was added to Severe microcephaly. Sources: Expert list
Q2_21_rating tags were added to gene: CTCF.
Mode of inheritance for gene: CTCF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTCF were set to 23746550; 30893510; 28619046
Phenotypes for gene: CTCF were set to Mental retardation, autosomal dominant 21, OMIM:615502
Review for gene: CTCF was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. New gene added by Zornitza Stark (however, it was added under the gene symbol CTSF but should be CTCF) with the following review:

"Recommended gene rating: Green
PMID: 23746550
- 4 probands, 2x PTV, 1x missense, 1x 280kb deletion (all de novo)
- OFCs ranges from -0.8 SD (the proband with the deletion) to -3.51 SD

PMID: 30893510
- 3 probands, de novo 2x PTV and 1x missense
- OFCs ranges from < -2 to < -3 SD

PMID: 28619046
- 1x proband with de novo fs
- head circumference was under 10th centle
Sources: Expert list
Created: 4 Sep 2020, 10:18 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation, autosomal dominant 21 (MIM#615502)

Publications

23746550
30893510
28619046

Variants in this GENE are reported as part of current diagnostic practice
Created: 4 Sep 2020, 10:18 a.m."

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Expert list
Severe microcephaly v2.135 CTSF Ivone Leong edited their review of gene: CTSF: Added comment: This gene has been tagged with "curated_removed" as it should be CTCF not CTSF gene added to this panel.; Changed rating: RED
Severe microcephaly v2.135 CTSF Ivone Leong Tag curated_removed tag was added to gene: CTSF.
Severe microcephaly v2.135 CTSF Ivone Leong changed review comment from: Comment on phenotypes: CTSF is no longer associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.; to: Comment on phenotypes: CTSF is not associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.
Severe microcephaly v2.135 CTSF Ivone Leong Added comment: Comment on phenotypes: CTSF is no longer associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.
Severe microcephaly v2.135 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Mental retardation, autosomal dominant 21, OMIM:615502 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362
Severe microcephaly v2.134 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Mental retardation, autosomal dominant 21 (MIM#615502) to Mental retardation, autosomal dominant 21, OMIM:615502
Optic neuropathy v2.40 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome to Wolfram syndrome 1, OMIM:222300
Optic neuropathy v2.39 WFS1 Eleanor Williams Publications for gene: WFS1 were set to
Optic neuropathy v2.38 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Monogenic diabetes v2.42 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27217304; 27185633
Monogenic diabetes v2.41 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Familial diabetes v1.61 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome, 222300 to Wolfram syndrome, OMIM:222300
Familial diabetes v1.60 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27217304; 27185633
Familial diabetes v1.59 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.62 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome, 222300; Deafness, autosomal dominant 6/14/38, 600965; Wolfram-like syndrome, autosomal dominant, 614296; {Diabetes mellitus, noninsulin-dependent, association with}, 125853; ?Cataract 41,116400; Deafness,autosomal dominant 6/14/38, 600965; Wolfram syndrome, 222300; {Diabetes mellitus, noninsulin-dependent,association with}; diabetes insipidus or optic atrophy to Wolfram syndrome, OMIM:222300; Deafness, autosomal dominant 6/14/38, OMIM:600965; Wolfram-like syndrome, autosomal dominant, OMIM:614296; {Diabetes mellitus, noninsulin-dependent, association with}, OMIM:125853; ?Cataract 41, OMIM:116400; diabetes insipidus or optic atrophy
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.61 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27217304; 27185633
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.60 WFS1 Eleanor Williams commented on gene: WFS1
Neurodegenerative disorders, adult onset v2.174 SNCB Eleanor Williams reviewed gene: SNCB: Rating: AMBER; Mode of pathogenicity: None; Publications: 33760043, 15365127, 12641375; Phenotypes: Dementia, Lewy body, OMIM:127750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.48 SNCB Eleanor Williams reviewed gene: SNCB: Rating: AMBER; Mode of pathogenicity: None; Publications: 33760043, 15365127, 12641375; Phenotypes: Dementia, Lewy body, OMIM:127750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe insulin resistance and lipodystrophy syndromes v2.12 OTULIN Ivone Leong Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099 to Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099
Severe insulin resistance and lipodystrophy syndromes v2.11 FBN1 Ivone Leong Phenotypes for gene: FBN1 were changed from Marfan lipodystrophy syndrome, MIM# 616914 to Marfan lipodystrophy syndrome, OMIM:616914
Severe insulin resistance and lipodystrophy syndromes v2.10 KCNJ6 Ivone Leong Phenotypes for gene: KCNJ6 were changed from Keppen-Lubinsky syndrome, MIM# 614098; MONDO:0013572 to Keppen-Lubinsky syndrome, OMIM:614098; Keppen-Lubinsky syndrome, MONDO:0013572
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Tag watchlist tag was added to gene: ZCCHC8.
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Classified gene: ZCCHC8 as Amber List (moderate evidence)
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Familial pulmonary fibrosis v1.14 ZCCHC8 Ivone Leong Phenotypes for gene: ZCCHC8 were changed from Pulmonary fibrosis to ?Pulmonary fibrosis and/or bone marrow failure, telomere-related, 5, OMIM:618674
Primary lymphoedema v2.12 ARAP3 Ivone Leong Classified gene: ARAP3 as Amber List (moderate evidence)
Primary lymphoedema v2.12 ARAP3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary lymphoedema v2.12 ARAP3 Ivone Leong Gene: arap3 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v2.11 ARAP3 Ivone Leong Tag watchlist tag was added to gene: ARAP3.
Primary lymphoedema v2.11 RORC Ivone Leong Classified gene: RORC as Amber List (moderate evidence)
Primary lymphoedema v2.11 RORC Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been rated Amber.
Primary lymphoedema v2.11 RORC Ivone Leong Gene: rorc has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v2.10 RORC Ivone Leong Tag watchlist tag was added to gene: RORC.
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Classified gene: CSNK2A1 as Amber List (moderate evidence)
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Gene: csnk2a1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.132 CSNK2A1 Ivone Leong Tag Q2_21_rating tag was added to gene: CSNK2A1.
Severe microcephaly v2.132 CSNK2A1 Ivone Leong Phenotypes for gene: CSNK2A1 were changed from Okur-Chung neurodevelopmental syndrome MIM#617062 to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Severe microcephaly v2.131 CHAMP1 Ivone Leong Classified gene: CHAMP1 as Amber List (moderate evidence)
Severe microcephaly v2.131 CHAMP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.131 CHAMP1 Ivone Leong Gene: champ1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.130 CHAMP1 Ivone Leong Tag Q2_21_rating tag was added to gene: CHAMP1.
Severe microcephaly v2.130 CHAMP1 Ivone Leong Added comment: Comment on publications: PMID: 26751395 additional paper
Severe microcephaly v2.130 CHAMP1 Ivone Leong Publications for gene: CHAMP1 were set to 27148580; 26340335
Severe microcephaly v2.129 CHAMP1 Ivone Leong Phenotypes for gene: CHAMP1 were changed from Mental retardation, autosomal dominant 40 (MIM#616579) to Mental retardation, autosomal dominant 40, OMIM:616579
Severe microcephaly v2.128 CEP63 Ivone Leong commented on gene: CEP63
Severe microcephaly v2.128 CEP63 Ivone Leong Tag Q2_21_expert_review tag was added to gene: CEP63.
Severe microcephaly v2.128 CEP57 Ivone Leong Classified gene: CEP57 as Amber List (moderate evidence)
Severe microcephaly v2.128 CEP57 Ivone Leong Gene: cep57 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.127 CEP57 Ivone Leong gene: CEP57 was added
gene: CEP57 was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: CEP57.
Mode of inheritance for gene: CEP57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP57 were set to 24259107; 30010053; 21552266
Phenotypes for gene: CEP57 were set to Mosaic variegated aneuploidy syndrome 2, OMIM:614114
Review for gene: CEP57 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are 7 reported cases (9 affected individuals) with homozygous/compound heterzygous variants in this gene (4 variants - c.520_521delGA, c.915_925dup11, c241C>T, c.697delA). Microcephaly is reported in 5/9 individuals (4 families - in 1 family with 2 affected sibs only 1 sib had microcephaly). Those with microcephaly are either compound heterozygous or homozygous for c.915_925dup11 (Mexican, Caucasian, Moroccan origin). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Severe microcephaly v2.126 TRIP13 Ivone Leong Classified gene: TRIP13 as Amber List (moderate evidence)
Severe microcephaly v2.126 TRIP13 Ivone Leong Gene: trip13 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.125 TRIP13 Ivone Leong gene: TRIP13 was added
gene: TRIP13 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: TRIP13.
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP13 were set to 28553959
Phenotypes for gene: TRIP13 were set to Mosaic variegated aneuploidy syndrome 3, OMIM:617598
Review for gene: TRIP13 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 28553959 describes 6 probands with variants in this gene. 3/6 probands had microcephaly (2 of these probands have the same homozygous variant and may be due to a founder effect). Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been rated Amber for now.
Sources: Literature
Severe microcephaly v2.124 BUB1B Ivone Leong Classified gene: BUB1B as Amber List (moderate evidence)
Severe microcephaly v2.124 BUB1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.124 BUB1B Ivone Leong Gene: bub1b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.123 BUB1B Ivone Leong Tag Q2_21_rating tag was added to gene: BUB1B.
Severe microcephaly v2.123 BUB1B Ivone Leong Phenotypes for gene: BUB1B were changed from Mosaic variegated aneuploidy syndrome 1 (MIM#257300) to Mosaic variegated aneuploidy syndrome 1, OMIM:257300
Severe microcephaly v2.122 BPTF Ivone Leong Classified gene: BPTF as Amber List (moderate evidence)
Severe microcephaly v2.122 BPTF Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-diseas association. This gene should be rated Green at the next review.
Severe microcephaly v2.122 BPTF Ivone Leong Gene: bptf has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.121 BPTF Ivone Leong Tag Q2_21_rating tag was added to gene: BPTF.
Severe microcephaly v2.121 BPTF Ivone Leong Added comment: Comment on publications: PMID:33522091 additonal paper describing 12/20 unrelated cases with microcephaly
Severe microcephaly v2.121 BPTF Ivone Leong Publications for gene: BPTF were set to 28942966
Severe microcephaly v2.120 BPTF Ivone Leong Phenotypes for gene: BPTF were changed from Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755 to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, OMIM:617755
White matter disorders and cerebral calcification - childhood onset v1.59 AARS Ivone Leong commented on gene: AARS: Added new-gene-name tag, new approved HGNC gene symbol for AARS is AARS1
White matter disorders and cerebral calcification - childhood onset v1.59 AARS Ivone Leong Tag new-gene-name tag was added to gene: AARS.
Severe microcephaly v2.119 AARS Ivone Leong Tag Q2_21_rating tag was added to gene: AARS.
White matter disorders and cerebral calcification - childhood onset v1.59 AARS Ivone Leong Classified gene: AARS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.59 AARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.59 AARS Ivone Leong Gene: aars has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.58 AARS Ivone Leong Tag Q2_21_rating tag was added to gene: AARS.
Severe microcephaly v2.119 AARS Ivone Leong Classified gene: AARS as Amber List (moderate evidence)
Severe microcephaly v2.119 AARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.119 AARS Ivone Leong Gene: aars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.118 AARS Ivone Leong commented on gene: AARS
Severe microcephaly v2.118 AARS Ivone Leong Tag new-gene-name tag was added to gene: AARS.
Intellectual disability v3.1062 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1062 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from Primordial dwarfism; motor and speech delay; intellectual disability; global developmental delay. to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Intellectual disability v3.1061 WDR4 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR4.
Intellectual disability v3.1061 WDR4 Ivone Leong Publications for gene: WDR4 were set to 29597095; 26416026
Severe microcephaly v2.118 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.118 WDR4 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR4.
Severe microcephaly v2.118 WDR4 Ivone Leong Publications for gene: WDR4 were set to 26416026; 29597095; 30079490; 29597095
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 IL6ST Eleanor Williams reviewed gene: IL6ST: Rating: ; Mode of pathogenicity: None; Publications: 33517393; Phenotypes: ; Mode of inheritance: None
Unexplained young onset end-stage renal disease v1.18 OCRL Eleanor Williams Publications for gene: OCRL were set to 21249396; 17384968
Unexplained young onset end-stage renal disease v1.17 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from LOWE OCULOCEREBRORENAL SYNDROME #309000; Dent disease 2 #300555 to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555
Unexplained young onset end-stage renal disease v1.16 OCRL Eleanor Williams edited their review of gene: OCRL: Added comment: Genotype/Phenotype information: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explain symptom heterogeneity and may help stratify patients; Changed publications: 33517444
Undiagnosed metabolic disorders v1.456 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Dent disease 2 300555; Lowe syndrome 309000 to Dent disease 2, OMIM:300555; Lowe syndrome, OMIM:309000
Undiagnosed metabolic disorders v1.455 OCRL Eleanor Williams Publications for gene: OCRL were set to 27604308; 8504307; 9632163; 9632163; 15627218; 27625797
Undiagnosed metabolic disorders v1.454 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.129 OCRL Eleanor Williams Publications for gene: OCRL were set to 27604308; 8504307; 9632163; 9632163; 15627218; 27625797
Likely inborn error of metabolism v2.128 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Dent disease 2 300555; Lowe syndrome 309000 to Dent disease 2, OMIM:300555; Lowe syndrome, OMIM:309000
Likely inborn error of metabolism v2.127 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.648 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from DENT DISEASE TYPE 2; LOWE OCULOCEREBRORENAL SYNDROME to Dent disease 2, OMIM:300555; Lowe syndrome, OMIM:309000
Fetal anomalies v1.647 OCRL Eleanor Williams Publications for gene: OCRL were set to
Fetal anomalies v1.646 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1060 OCRL Eleanor Williams Publications for gene: OCRL were set to
Intellectual disability v3.1059 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Proteinuric renal disease v2.50 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from LOWE OCULOCEREBRORENAL SYNDROME #309000; Dent disease 2 #300555 to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555
Dystonia, chorea or related movement disorder, childhood onset v1.96 FITM2 Sarah Leigh edited their review of gene: FITM2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least four variants reported in at least three unrelated cases. Supportive drosophila model.; Changed rating: GREEN
Proteinuric renal disease v2.49 OCRL Eleanor Williams commented on gene: OCRL: Genotype/Phenotype information: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explains symptom heterogeneity and may help stratify patients.
Leukodystrophy, adult onset v1.10 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000 to Lowe syndrome, OMIM:309000
Leukodystrophy, adult onset v1.9 OCRL Eleanor Williams Publications for gene: OCRL were set to 27159321; 25527826; 28334938; 20301621; 24357685
Leukodystrophy, adult onset v1.8 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.74 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome; Confirmed DD gene for LOWE OCULOCEREBRORENAL SYNDROME to Lowe syndrome, OMIM:309000; Confirmed DD gene for LOWE OCULOCEREBRORENAL SYNDROME
Dystonia, chorea or related movement disorder, childhood onset v1.96 FITM2 Sarah Leigh Tag Q2_21_rating tag was added to gene: FITM2.
Dystonia, chorea or related movement disorder, childhood onset v1.96 FITM2 Sarah Leigh Classified gene: FITM2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.96 FITM2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.96 FITM2 Sarah Leigh Gene: fitm2 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.73 OCRL Eleanor Williams Publications for gene: OCRL were set to
Bilateral congenital or childhood onset cataracts v2.72 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Nephrocalcinosis or nephrolithiasis v2.18 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000; Dent disease 2, 300555; As for CLCN5 (Nephrocalcinosis with low molecular weight proteinuria and pregressive CKD) but may include intellectual disability and other features of Lowe syndrome to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555; As for CLCN5 (Nephrocalcinosis with low molecular weight proteinuria and pregressive CKD) but may include intellectual disability and other features of Lowe syndrome
Nephrocalcinosis or nephrolithiasis v2.17 OCRL Eleanor Williams Publications for gene: OCRL were set to
Nephrocalcinosis or nephrolithiasis v2.16 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Glaucoma (developmental) v1.35 OCRL Eleanor Williams Publications for gene: OCRL were set to 19168822
Glaucoma (developmental) v1.34 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.95 FITM2 Sarah Leigh Phenotypes for gene: FITM2 were changed from Siddiqi syndrome MIM#618635; dystonia; deafness to Siddiqi syndrome OMIM:618635; siddiqi syndrome MONDO:0032842
Dystonia, chorea or related movement disorder, childhood onset v1.94 SCN1A Sarah Leigh Tag Q2_21_phenotype tag was added to gene: SCN1A.
Dystonia, chorea or related movement disorder, childhood onset v1.94 SCN1A Sarah Leigh edited their review of gene: SCN1A: Added comment: A non-Dravet syndrome epileptic encephalopathy phenotype associated with SCN1A variants. Eight cases carriers of p.Thr226Met shared this non-typical phenotype. This phenotype is not represented in OMIM, but they have been notified of the reporting publication (PMID 28794249), additional phenotype may be added to OMIM in the future.; Changed rating: GREEN
Primary lymphoedema v2.10 RORC Ivone Leong Phenotypes for gene: RORC were changed from Lymphoedema to Lymphoedema, MONDO:0019297
Primary lymphoedema v2.9 ARAP3 Ivone Leong Phenotypes for gene: ARAP3 were changed from Lymphoedema to Lymphoedema, MONDO:0019297
Retinal disorders v2.185 FAM57B Ivone Leong Classified gene: FAM57B as Amber List (moderate evidence)
Retinal disorders v2.185 FAM57B Ivone Leong Added comment: Comment on list classification: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.185 FAM57B Ivone Leong Gene: fam57b has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.94 SCN1A Sarah Leigh Classified gene: SCN1A as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.94 SCN1A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.94 SCN1A Sarah Leigh Gene: scn1a has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.184 FAM57B Ivone Leong Tag Q2_21_rating tag was added to gene: FAM57B.
Dystonia, chorea or related movement disorder, childhood onset v1.93 SCN1A Sarah Leigh Publications for gene: SCN1A were set to 19332696; 16054936
Intellectual disability v3.1059 CDH11 Arina Puzriakova Phenotypes for gene: CDH11 were changed from Elsahy-Waters syndrome to Elsahy-Waters syndrome, OMIM:211380; Teebi hypertelorism syndrome
Intellectual disability v3.1058 CDH11 Arina Puzriakova Publications for gene: CDH11 were set to 27431290; 29271567
Ataxia and cerebellar anomalies - childhood onset v2.156 SCN1A Sarah Leigh edited their review of gene: SCN1A: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in unrelated cases.; Changed rating: GREEN
Intellectual disability v3.1057 CDH11 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with biallelic variants well-established, with ID reported in all cases to date. On the other hand, DD/ID is variable in individuals with monoallelic variants (PMID: 33811546) - 7/19 cases (4 families) presented a developmental phenotype including very mild speech delays in 5/7, mild-moderate DD in 1/7, and global delay in 1/7 individuals.

Overall, given the mostly mild degree of cognitive delay, as well as intra- and interfamilial reduced penetrance of this feature, there is currently not enough evidence to rate as Green on this panel for the monoallelic disease.
Intellectual disability v3.1057 CDH11 Arina Puzriakova Mode of inheritance for gene: CDH11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.156 SCN1A Sarah Leigh Tag Q2_21_rating tag was added to gene: SCN1A.
Ataxia and cerebellar anomalies - childhood onset v2.156 SCN1A Sarah Leigh Publications for gene: SCN1A were set to 27264139; 27817982; 28732259
Ataxia and cerebellar anomalies - childhood onset v2.155 SCN1A Sarah Leigh Classified gene: SCN1A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.155 SCN1A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.155 SCN1A Sarah Leigh Gene: scn1a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.117 WDR4 Ivone Leong Publications for gene: WDR4 were set to 26416026; 29597095
Severe microcephaly v2.116 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from MPD; microcephalic primordial dwarfism to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Severe microcephaly v2.115 WDR37 Ivone Leong Classified gene: WDR37 as Amber List (moderate evidence)
Severe microcephaly v2.115 WDR37 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support this gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.115 WDR37 Ivone Leong Gene: wdr37 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.114 WDR37 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR37.
Ataxia and cerebellar anomalies - childhood onset v2.154 SCN1A Sarah Leigh Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208 to Dravet syndrome OMIM:607208; developmental and epileptic encephalopathy, 6 MONDO:0100079
Severe microcephaly v2.114 WDR37 Ivone Leong Phenotypes for gene: WDR37 were changed from Neurooculocardiogenitourinary syndrome MIM#618652 to Neurooculocardiogenitourinary syndrome, OMIM:618652
Proteinuric renal disease v2.49 APOL1 Eleanor Williams Publications for gene: APOL1 were set to 20647424; 23766536
Proteinuric renal disease v2.48 APOL1 Eleanor Williams edited their review of gene: APOL1: Added comment: PMID: 33517446 - Ge et al 2021 - demonstrate a mouse model to study APOL1 risk variants associated susceptibility to NFAT-mediated FSGS. They provide evidence that APOL1 G1 induced glomerular lipid accumulation correlates with loss of renal function and confirm that APOL1 G1/G2 risk variant is associated with mitochondrial dysfunction.; Changed publications: 33517446
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Tag Q2_21_rating was removed from gene: UFSP2.
Tag founder-effect tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208; 28892125; 26428751; 32755715
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Classified gene: UFSP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Green List (High Evidence).
Intellectual disability v3.1056 HTT Eleanor Williams changed review comment from: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.; to: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date (PMID: 27329733/33432339 and 26740508) with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.
Intellectual disability v3.1056 HTT Eleanor Williams reviewed gene: HTT: Rating: ; Mode of pathogenicity: None; Publications: 33432339; Phenotypes: Lopes-Maciel-Rodan syndrome OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection v1.112 PKD1 Dmitrijs Rots reviewed gene: PKD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Thoracic aortic aneurysm or dissection v1.112 PKD2 Dmitrijs Rots reviewed gene: PKD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia, childhood onset v2.30 FAR1 Arina Puzriakova Classified gene: FAR1 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.30 FAR1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update
Hereditary spastic paraplegia, childhood onset v2.30 FAR1 Arina Puzriakova Gene: far1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.29 FAR1 Arina Puzriakova gene: FAR1 was added
gene: FAR1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q2_21_rating tags were added to gene: FAR1.
Mode of inheritance for gene: FAR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FAR1 were set to 25439727; 30561787; 33239752
Phenotypes for gene: FAR1 were set to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Review for gene: FAR1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants (PMID: 33239752). Paediatric onset.
Sources: Literature
Skeletal dysplasia v2.97 UFSP2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases with skeletal dysplasia (OMIM:142669 & OMIM:617974). Supportive functional studies presented for one of the variants (PMID 26428751).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases with skeletal dysplasia (OMIM:142669 & OMIM:617974), within the UFSP2 C-terminal C78 peptidase domain, which is required for its catalytic activity. Supportive functional studies presented for one of the variants (PMID 26428751) .
Ataxia and cerebellar anomalies - childhood onset v2.153 TGM6 Ivone Leong commented on gene: TGM6
Ataxia and cerebellar anomalies - childhood onset v2.153 TGM6 Ivone Leong Tag Q2_21_rating tag was added to gene: TGM6.
Ataxia and cerebellar anomalies - childhood onset v2.153 TGM6 Ivone Leong Tag Q2_21_expert_review tag was added to gene: TGM6.
Ataxia and cerebellar anomalies - childhood onset v2.153 TGM6 Ivone Leong Phenotypes for gene: TGM6 were changed from Spinocerebellar ataxia 35, 613908 to Spinocerebellar ataxia 35, OMIM:613908
Ataxia and cerebellar anomalies - childhood onset v2.152 TGM6 Ivone Leong Publications for gene: TGM6 were set to 32426513; 30670339
Ataxia and cerebellar anomalies - childhood onset v2.151 TGM6 Ivone Leong Publications for gene: TGM6 were set to
Ataxia and cerebellar anomalies - childhood onset v2.150 TDP2 Ivone Leong Tag Q2_21_rating tag was added to gene: TDP2.
Ataxia and cerebellar anomalies - childhood onset v2.150 TDP2 Ivone Leong Classified gene: TDP2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.150 TDP2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.150 TDP2 Ivone Leong Gene: tdp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208
Skeletal dysplasia v2.97 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 28892125; 26428751; 32755715
Skeletal dysplasia v2.96 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: A biallelic variant rs142500730 has been associated with pediatric neurodevelopmental anomalies and epilepsy (PMID 33473208).
Skeletal dysplasia v2.96 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from ?Beukes Hip Dysplasia OMIM:142669; hip dysplasia, Beukes type MONDO:0007726; ?Spondyloepimetaphyseal dysplasia, Di Rocco type OMIM:617974; spondyloepimetaphyseal dysplasia, di rocco type MONDO:0060702 to ?Beukes Hip Dysplasia OMIM:142669; hip dysplasia, Beukes type MONDO:0007726; ?Spondyloepimetaphyseal dysplasia, Di Rocco type OMIM:617974; spondyloepimetaphyseal dysplasia, di rocco type MONDO:0060702
Skeletal dysplasia v2.95 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Skeletal dysplasia v2.95 UFSP2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal dysplasia v2.95 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.94 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Skeletal dysplasia v2.94 UFSP2 Sarah Leigh reviewed gene: UFSP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants (PMID: 33239752)
Sources: Literature; to: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants (PMID: 33239752)
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova Classified gene: FAR1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova Gene: far1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.71 FAR1 Arina Puzriakova gene: FAR1 was added
gene: FAR1 was added to Cataracts. Sources: Literature
Q2_21_rating tags were added to gene: FAR1.
Mode of inheritance for gene: FAR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FAR1 were set to 25439727; 30561787; 33239752
Phenotypes for gene: FAR1 were set to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Review for gene: FAR1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants (PMID: 33239752)
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.149 SPG7 Ivone Leong Tag Q2_21_expert_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - childhood onset v2.149 SPG7 Ivone Leong edited their review of gene: SPG7: Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID:33774748. Age of onset reported ranged from 12-61 yo (mean age = 39.1). 25 unrelated families of Irish descent.
PMID:32161564. Age of onset 25 - 45 yo.
PMID:31068484. Age of onset 35.5 +/- 14.3 years (mean age = 50.4). 241 patients were part of the study.
PMID:23065789. Age of onset 10 - 45 yo. 137 patients were part of the study.

As the age of onset is quite a wide range this gene will remain Green to ensure edge cases are identified. This gene has been tagged for GMS expert review on whether this gene's rating needs to be changed.; Changed publications: 33774748, 32161564, 31068484, 23065789
Dilated and arrhythmogenic cardiomyopathy v1.24 RHBDF1 Ivone Leong Classified gene: RHBDF1 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.24 RHBDF1 Ivone Leong Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.23 RHBDF1 Ivone Leong gene: RHBDF1 was added
gene: RHBDF1 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
watchlist tags were added to gene: RHBDF1.
Mode of inheritance for gene: RHBDF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHBDF1 were set to 32870709
Review for gene: RHBDF1 was set to AMBER
Added comment: This gene is rated Amber on the Cardiomyopathies - including childhood onset (Version 1.39) panel with the following reviews:

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 20 Apr 2021"

"Three families reported with homozygous variants in this gene and onset of DCM in infancy/childhood. Two of the families had the same truncating variant, indicative of founder effect, and one family had a homozygous missense variant. Sources: Literature
Zornitza Stark (Australian Genomics), 16 Apr 2021"
Sources: Literature
Intellectual disability v3.1056 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 25439727
Intellectual disability v3.1055 FAR1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: FAR1.
Tag Q2_21_MOI tag was added to gene: FAR1.
Intellectual disability v3.1055 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: ; Mode of inheritance: None
Paediatric or syndromic cardiomyopathy v1.39 NRAP Ivone Leong Classified gene: NRAP as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.39 NRAP Ivone Leong Gene: nrap has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.38 NRAP Ivone Leong gene: NRAP was added
gene: NRAP was added to Cardiomyopathies - including childhood onset. Sources: Literature
Q2_21_rating tags were added to gene: NRAP.
Mode of inheritance for gene: NRAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRAP were set to 30384889; 33534821; 28611399; https://doi.org/10.1101/2020.10.12.20211474; 32870709
Phenotypes for gene: NRAP were set to Dilated cardiomyopathy, MONDO:0005021 Edit
Review for gene: NRAP was set to GREEN
Added comment: This gene is Green on the Dilated cardiomyopathy - adult and teen (Version 1.22) with the following reviews:

"This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases of patients with variants in this gene and having DCM. https://doi.org/10.1101/2020.10.12.20211474 also describes a CRISPR knockout zebrafish which had a cardiac phenotype. Therefore, there is enough evidence to support a gene-disease association and this gene is recommended to be promoted Green at the next panel review. Sources: Literature
Ivone Leong (Genomics England Curator), 25 Feb 2021"

"Twenty unrelated families reported with childhood onset DCM. May be more appropriate for the paediatric cardiomyopathy panel."

As affected individuals have childhood onset DCM it was deemed appropriate to add this gene to this panel as well.
Sources: Literature
Skeletal dysplasia v2.94 UFSP2 Sarah Leigh Mode of inheritance for gene: UFSP2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v1.92 ADAMTS19 Ivone Leong Classified gene: ADAMTS19 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.92 ADAMTS19 Ivone Leong Gene: adamts19 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.91 ADAMTS19 Ivone Leong gene: ADAMTS19 was added
gene: ADAMTS19 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_21_rating, Q2_21_phenotype tags were added to gene: ADAMTS19.
Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS19 were set to 31844321; 32323311
Phenotypes for gene: ADAMTS19 were set to Non-syndromic heart valve disease; heart valve disease, MONDO:0002869
Review for gene: ADAMTS19 was set to AMBER
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. It is a Green gene on the Familial non syndromic congenital heart disease (Version 1.60) panel with the following reviews:

"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
Zornitza Stark (Australian Genomics), 1 Jul 2020"

"PMID: 31844321; Wünnemann 2020: 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 Sources: Literature
Zornitza Stark (Australian Genomics), 1 May 2020"

After consulting the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to GMS specialist review panel to consider whether the isolated phenotype is appropriate for inclusion. If appropriate then this gene should be promoted to Green status.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 PLG Matthew Buckland gene: PLG was added
gene: PLG was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PLG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLG were set to PMID: 28795768
Phenotypes for gene: PLG were set to Non-C1 Hereditary Angioedema
Penetrance for gene: PLG were set to unknown
Review for gene: PLG was set to GREEN
Added comment: Bork et al. identified the exon9 mutation in PLG in four index families with normal-C1 hereditary angioedema and a further 9 families studied, with shared clinical features.
Sufficient information to ascribe causality.
Sources: Literature
Skeletal dysplasia v2.93 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Beukes Hip Dysplasia 142669, Spondyloepimetaphyseal dysplasia, Di Rocco type 617974 to ?Beukes Hip Dysplasia OMIM:142669; hip dysplasia, Beukes type MONDO:0007726; ?Spondyloepimetaphyseal dysplasia, Di Rocco type OMIM:617974; spondyloepimetaphyseal dysplasia, di rocco type MONDO:0060702
Skeletal dysplasia v2.92 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 28892125; 26428751
Laterality disorders and isomerism v1.45 BRWD1 Ivone Leong Classified gene: BRWD1 as Red List (low evidence)
Laterality disorders and isomerism v1.45 BRWD1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As only 1 case has situs inversus this gene has been added to this panel as a Red gene.

After discussion with the Genomics England Clinical Team it was decided that this gene would be better suited for the Respiratory ciliopathies including non-CF bronchiectasis (Version 1.45). This gene has been added as an Amber gene with a recommendation for Green status on that panel.
Laterality disorders and isomerism v1.45 BRWD1 Ivone Leong Gene: brwd1 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.45 BRWD1 Ivone Leong Classified gene: BRWD1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.45 BRWD1 Ivone Leong Gene: brwd1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.44 BRWD1 Ivone Leong gene: BRWD1 was added
gene: BRWD1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Q2_21_rating tags were added to gene: BRWD1.
Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRWD1 were set to 33389130
Phenotypes for gene: BRWD1 were set to Primary ciliary dyskinesia, asthenoteratozoospermia
Review for gene: BRWD1 was set to GREEN
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene was added to the Laterality disorders and isomerism (Version 1.44) panel by Zornitza Stark with the following review:

"Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-like" symptoms of reccurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls). Sources: Literature
Zornitza Stark (Australian Genomics), 7 Feb 2021"

After discussion with the Genomics England Clinical Team it was decided that this gene was better suited to this panel.
Sources: Literature
Laterality disorders and isomerism v1.44 NODAL Ivone Leong commented on gene: NODAL
Laterality disorders and isomerism v1.44 NODAL Ivone Leong Tag Q2_21_expert_review tag was added to gene: NODAL.
Laterality disorders and isomerism v1.44 NKX2-5 Ivone Leong Publications for gene: NKX2-5 were set to 25742962; 26805889
Laterality disorders and isomerism v1.43 NKX2-5 Ivone Leong edited their review of gene: NKX2-5: Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype.

PMID: 12414819 describes 2 unrelated families. Family 1: 4 family members with variant in NKX2-5 had atrial septum defect. One of these family members was also diagnosed with polyspenia, midline symmetrical liver, ascending colon and caecum were shifted to the midline and forwards with the small intestine on the left. Family 2: 3 affected family members had atrial septum defect.

PMID: 25118008 describes a proband with a frameshift variant in NKX2-5 with the following phenotypes: double outlet right ventricle, common AV canal, total anomalous pulmonary venous connection, asplenia, failure to thrive and short stature. The proband also had distorted organ position and liver was centrally located and spleen was not identied at 1 week of age. Also had intestinal malformation and underwent Ladd procedure and gastrostomy tube placement at 3 weeks. The authors in this paper notes that NKX2-5 variants are associated with cardiac malformations that are commonly seen in patients with heterotaxy (i.e. transposition of great artieries and double outlet right ventricle) and also with asplenia in some patients.

After discussion with the Genomics England Clinical Team it was decided that this gene should remain Amber on this panel.; Changed rating: AMBER; Changed publications: 12414819, 25118008
Cholestasis v1.83 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Cholestasis v1.83 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.82 AP1S1 Ivone Leong gene: AP1S1 was added
gene: AP1S1 was added to Cholestasis. Sources: Literature
Q2_21_rating tags were added to gene: AP1S1.
Mode of inheritance for gene: AP1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1S1 were set to 32306098; 15668823; 19057675; 23423674; 30244301
Phenotypes for gene: AP1S1 were set to Non-syndromic congenital intestinal failure; MEDNIK syndrome, OMIM:609313
Review for gene: AP1S1 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. This gene is also Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.40) with the following reviews:

" Established gene-disease association with MEDNIK syndrome - PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant - AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense variants. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"

"This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review."

After discussion with the Genomics England Clinical Team it was decided that this gene should also be included in this panel.
Sources: Literature
Monogenic hearing loss v2.162 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Monogenic hearing loss v2.162 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.161 AP1S1 Ivone Leong gene: AP1S1 was added
gene: AP1S1 was added to Hearing loss. Sources: Literature
Q2_21_rating tags were added to gene: AP1S1.
Mode of inheritance for gene: AP1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1S1 were set to 32306098; 15668823; 19057675; 23423674; 30244301
Phenotypes for gene: AP1S1 were set to Non-syndromic congenital intestinal failure; MEDNIK syndrome, OMIM:609313
Review for gene: AP1S1 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. This gene is also Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.40) with the following reviews:

" Established gene-disease association with MEDNIK syndrome - PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant - AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense variants. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"

"This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review."

After discussion with the Genomics England Clinical Team it was decided that this gene should also be included in this panel.
Sources: Literature
Intellectual disability v3.1055 HERC2 Arina Puzriakova Publications for gene: HERC2 were set to 23065719
Intestinal failure or congenital diarrhoea v1.40 AP1S1 Ivone Leong Publications for gene: AP1S1 were set to 32306098; 15668823, 19057675, 23423674, 30244301
Intellectual disability v3.1054 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 to Mental retardation, autosomal recessive 38, OMIM:615516
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.

After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.334 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 (MIM 615516) to Mental retardation, autosomal recessive 38, OMIM:615516
Intestinal failure or congenital diarrhoea v1.38 AP1S1 Ivone Leong Tag Q2_21_rating tag was added to gene: AP1S1.
Intestinal failure or congenital diarrhoea v1.38 AP1S1 Ivone Leong Phenotypes for gene: AP1S1 were changed from Non-syndromic congenital intestinal failure to Non-syndromic congenital intestinal failure; MEDNIK syndrome, OMIM:609313
Intestinal failure or congenital diarrhoea v1.37 AP1S1 Ivone Leong Publications for gene: AP1S1 were set to 32306098
VACTERL-like phenotypes v1.31 PLVAP Ivone Leong Classified gene: PLVAP as Green List (high evidence)
VACTERL-like phenotypes v1.31 PLVAP Ivone Leong Gene: plvap has been classified as Green List (High Evidence).
CAKUT v1.162 PLVAP Ivone Leong Classified gene: PLVAP as Green List (high evidence)
CAKUT v1.162 PLVAP Ivone Leong Gene: plvap has been classified as Green List (High Evidence).
VACTERL-like phenotypes v1.30 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to VACTERL-like phenotypes. Sources: Literature
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
CAKUT v1.161 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to CAKUT. Sources: Literature
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
Intellectual disability v3.1053 NUBPL Arina Puzriakova Phenotypes for gene: NUBPL were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 21, OMIM:618242
Paediatric disorders - additional genes v1.90 PLVAP Ivone Leong Classified gene: PLVAP as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.90 PLVAP Ivone Leong Gene: plvap has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.89 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to Paediatric disorders - additional genes. Sources: Literature
Q2_21_rating tags were added to gene: PLVAP.
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
Paediatric disorders - additional genes v1.88 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.88 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.87 FOXP4 Ivone Leong gene: FOXP4 was added
gene: FOXP4 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_21_phenotype tags were added to gene: FOXP4.
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not in OMIM.

This gene is present as an Amber gene on the Intellectual disability panel (Version 3.1052) with the following reviews:

"This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel? Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here. Sources: Literature
Zornitza Stark (Australian Genomics), 4 Nov 2020"

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 4 Dec 2020"

After discussion with the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to review by the GMS specialist group.
Sources: Literature
Fetal anomalies v1.646 FOXP4 Ivone Leong Tag Q2_21_rating was removed from gene: FOXP4.
Fetal anomalies v1.646 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Fetal anomalies v1.646 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.645 FOXP4 Ivone Leong gene: FOXP4 was added
gene: FOXP4 was added to Fetal anomalies. Sources: Literature
Q2_21_rating, Q2_21_phenotype tags were added to gene: FOXP4.
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not in OMIM.

This gene is present as an Amber gene on the Intellectual disability panel (Version 3.1052) with the following reviews:

"This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel? Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here. Sources: Literature
Zornitza Stark (Australian Genomics), 4 Nov 2020"

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 4 Dec 2020"

After discussion with the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to review by the GMS specialist group.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.28 HPDL Cristina Dias reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32707086, 33188300; Phenotypes: microcephaly, spastic paraplegia, seizures, demyelinating neuropathy, regression, developmental delay, chronic progression, movement disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1052 INPP4A Arina Puzriakova Phenotypes for gene: INPP4A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; Seizures
Intellectual disability v3.1051 INPP4A Arina Puzriakova Publications for gene: INPP4A were set to 21937992
Intellectual disability v3.1050 INPP4A Arina Puzriakova Classified gene: INPP4A as Amber List (moderate evidence)
Intellectual disability v3.1050 INPP4A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. 2 unrelated families with severe ID and biallelic variants in this gene reported to date (PMIDs: 25338135; 31978615)
Intellectual disability v3.1050 INPP4A Arina Puzriakova Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1049 UBE4A Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.; to: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - PMID:33420346 report 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Tag Q2_21_rating tag was added to gene: UBE4A.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Classified gene: UBE4A as Amber List (moderate evidence)
Intellectual disability v3.1049 UBE4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Gene: ube4a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova changed review comment from: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.; to: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline if this gene is upgraded to Green on this panel in the future.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Added comment: Comment on list classification: Rating Amber with monoallelic MOI, awaiting further cases with seizures (2/3 de novo cases with epilepsy - PMID: 33711248). Currently 'Red' evidence level for biallelic form.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.331 NCDN Arina Puzriakova gene: NCDN was added
gene: NCDN was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NCDN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to AMBER
Added comment: NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. All 3 sibs had generalised seizures (fever induced in 2), while 2/3 individuals with heterozygous variants developed epileptic spasms presenting several times per day prior to treatment. Supportive functional data included.
Sources: Literature
Intellectual disability v3.1048 NCDN Arina Puzriakova Tag Q2_21_rating tag was added to gene: NCDN.
Intellectual disability v3.1048 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
Intellectual disability v3.1048 NCDN Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene as Green with 'monoallelic' MOI at next GMS panel update.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. Severity of ID in individuals with heterozygous variants is severe, moderate, and mild (but also learning disabilities), respectively. ID in the 3 sibs was determined as mild. Supportive functional data included.

NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.
Intellectual disability v3.1048 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1047 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.1047 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.41 MAPKAPK5 Arina Puzriakova Classified gene: MAPKAPK5 as Amber List (moderate evidence)
Limb disorders v2.41 MAPKAPK5 Arina Puzriakova Gene: mapkapk5 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.40 MAPKAPK5 Arina Puzriakova gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 33442026
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism; Synpolydactyly
Review for gene: MAPKAPK5 was set to AMBER
Added comment: MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.

- PMID: 33442026 (2021) - 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Rating Amber, awaiting further cases.
Sources: Literature
Intellectual disability v3.1046 MAPKAPK5 Arina Puzriakova Tag watchlist tag was added to gene: MAPKAPK5.
Intellectual disability v3.1046 MAPKAPK5 Arina Puzriakova Publications for gene: MAPKAPK5 were set to 3344202
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Classified gene: MAPKAPK5 as Amber List (moderate evidence)
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber, awaiting further cases (added watchlist tag)

- PMID: 33442026 report on 2 unrelated families with a comparable phenotype including severe GDD, who harbour different homozygous truncating variants in MAPKAPK5. Some functional evidence indicating the variants impact expression and function of MAPKAPK5 protein.

MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Gene: mapkapk5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.113 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Severe microcephaly v2.113 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.112 COPB1 Arina Puzriakova gene: COPB1 was added
gene: COPB1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Added comment: COPB1 is associated with a relevant phenotype in OMIM (MIM# 619255) and has a 'possible' disease confidence rating for 'COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly' in Gene2Phenotype.

- PMID: 33632302 (2021) - six individuals from two unrelated families with different homozygous variants in this gene. Affected patients developed cataracts, severe ID and variable microcephaly - at least 1 individual from each family with microcephaly of relevant severity to this panel (HC ≥ -3SD). Some supportive functional data.

Rating Amber, awaiting further cases.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.70 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.70 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.69 COPB1 Arina Puzriakova gene: COPB1 was added
gene: COPB1 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Review for gene: COPB1 was set to AMBER
Added comment: COPB1 is associated with a relevant phenotype in OMIM (MIM# 619255) and has a 'possible' disease confidence rating for 'COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly' in Gene2Phenotype.

- PMID: 33632302 (2021) - six individuals from two unrelated families with different homozygous variants in this gene. All affected patients developed cataracts, among other features such as severe ID and variable microcephaly. Some supportive functional data.

Rating Amber, awaiting further cases.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.92 SCN1A Dmitrijs Rots reviewed gene: SCN1A: 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: 28794249; Phenotypes: seizures, developmental delay, dystonia, choreoathetosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1044 COPB1 Arina Puzriakova Tag watchlist tag was added to gene: COPB1.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Intellectual disability v3.1044 COPB1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33632302 reports on six individuals from two unrelated families with different homozygous variants in this gene. All affected patients had severe ID. Rating Amber, awaiting further cases.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1043 COPB1 Arina Puzriakova Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Dystonia, chorea or related movement disorder, childhood onset v1.92 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Cutis laxa, autosomal dominant 3 616603; Cutis laxa, autosomal recessive, type IIIA 219150; Spastic paraplegia 9A, autosomal dominant 601162; Spastic paraplegia 9B, autosomal recessive 616586 to Cutis laxa, autosomal dominant 3 OMIM:616603; cutis laxa, autosomal dominant 3 MONDO:0014706; Cutis laxa, autosomal recessive, type IIIA OMIM:219150; ALDH18A1-related de Barsy syndromeMONDO:0009053; Spastic paraplegia 9A, autosomal dominant OMIM:601162; hereditary spastic paraplegia 9A MONDO:0011006; Spastic paraplegia 9B, autosomal recessive OMIM:616586; autosomal recessive complex spastic paraplegia type 9B MONDO:0014702
Dystonia, chorea or related movement disorder, childhood onset v1.91 ALDH18A1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ALDH18A1.
Cerebral vascular malformations v2.50 ANGPTL6 Sarah Leigh edited their review of gene: ANGPTL6: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 9 variants reported in at least 11 families with Familial Intracranial Aneurysm. Expression and secretion studies have been performed for NM_031917.2. c.1378A>T, p.Lys460Ter, showing that although it is expressed it is not secreted.; Changed rating: GREEN
Cerebral vascular malformations v2.50 ANGPTL6 Sarah Leigh Tag Q2_21_rating tag was added to gene: ANGPTL6.
Cerebral vascular malformations v2.50 ANGPTL6 Sarah Leigh Publications for gene: ANGPTL6 were set to 29304371; 33106390
Cerebral vascular malformations v2.49 ANGPTL6 Sarah Leigh Classified gene: ANGPTL6 as Amber List (moderate evidence)
Cerebral vascular malformations v2.49 ANGPTL6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Cerebral vascular malformations v2.49 ANGPTL6 Sarah Leigh Gene: angptl6 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.48 ANGPTL6 Sarah Leigh Phenotypes for gene: ANGPTL6 were changed from Cerebral aneurysm to brain aneurysm MONDO:0005291
Cystic kidney disease v2.26 FLCN Eleanor Williams Classified gene: FLCN as Amber List (moderate evidence)
Cystic kidney disease v2.26 FLCN Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, with a recommendation for green rating at the next GMS review.
Cystic kidney disease v2.26 FLCN Eleanor Williams Gene: flcn has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.25 FLCN Eleanor Williams Tag Q2_21_rating tag was added to gene: FLCN.
Cystic kidney disease v2.25 FLCN Eleanor Williams commented on gene: FLCN
Cystic kidney disease v2.25 FLCN Eleanor Williams Publications for gene: FLCN were set to PMID: 19785621; 31266032
Cystic kidney disease v2.24 FLCN Eleanor Williams Phenotypes for gene: FLCN were changed from renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma to Birt-Hogg-Dube syndrome, OMIM:135150; renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma
White matter disorders and cerebral calcification - childhood onset v1.58 FIG4 Eleanor Williams Classified gene: FIG4 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.58 FIG4 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating at the next GMS review as there are 4 cases with variants in this gene and a leukoencephalopathy phenotype, plus a supportive mouse model.
White matter disorders and cerebral calcification - childhood onset v1.58 FIG4 Eleanor Williams Gene: fig4 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.57 FIG4 Eleanor Williams Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J 611228; Yunis-Varon syndrome 216340; leukoencephalopathy to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Yunis-Varon syndrome, OMIM:216340; leukoencephalopathy, HP:0002352
White matter disorders and cerebral calcification - childhood onset v1.56 FIG4 Eleanor Williams Tag Q2_21_rating tag was added to gene: FIG4.
White matter disorders and cerebral calcification - childhood onset v1.56 FIG4 Eleanor Williams commented on gene: FIG4
White matter disorders and cerebral calcification - childhood onset v1.56 ERCC1 Eleanor Williams changed review comment from: 4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling. ; to: 4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child (CS20LO) was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling.
White matter disorders and cerebral calcification - childhood onset v1.56 ERCC1 Eleanor Williams Publications for gene: ERCC1 were set to 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure; 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome; 21612988
White matter disorders and cerebral calcification - childhood onset v1.55 ERCC1 Eleanor Williams edited their review of gene: ERCC1: Changed publications: 17273966, 23623389, 21612988, 33315086
White matter disorders and cerebral calcification - childhood onset v1.55 ERCC1 Eleanor Williams changed review comment from: 3 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - can't access paper. Not in PubMed but review by Gregg et al 2011 (PMID: 21612988) report that it describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.; to: 4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling.
Segmental overgrowth disorders - Deep sequencing v2.13 NLRP2 Sarah Leigh Classified gene: NLRP2 as Amber List (moderate evidence)
Segmental overgrowth disorders - Deep sequencing v2.13 NLRP2 Sarah Leigh Gene: nlrp2 has been classified as Amber List (Moderate Evidence).
Segmental overgrowth disorders - Deep sequencing v2.12 NLRP2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Maternal NLRP2 variants result in epigenitic disturbance at sites in trans, eg: IC2 in imprinting region at 11p15.5 (PMID 19300480).
Segmental overgrowth disorders - Deep sequencing v2.12 NLRP2 Sarah Leigh Mode of pathogenicity for gene: NLRP2 was changed from Other to Other
Segmental overgrowth disorders - Deep sequencing v2.11 NLRP2 Sarah Leigh gene: NLRP2 was added
gene: NLRP2 was added to Segmental overgrowth disorders. Sources: Literature
Mode of inheritance for gene: NLRP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NLRP2 were set to 26323243; 29574422; 19300480; 30877238; 33090377
Phenotypes for gene: NLRP2 were set to Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475
Mode of pathogenicity for gene: NLRP2 was set to Other
Review for gene: NLRP2 was set to AMBER
Added comment: Maternal bialliec variants may result in epigentic distubance of IC2 in imprinting region at 11p15.5 in trans, resulting in Beckwith-Wiedemann syndrome (PMID 19300480) and early embryonic arest, (causing infertility)(PMID 30877238). These findings are supported by a mouse knock out model (PMID 33090377). At least 9 human NLRP2 variants have been identified in families with the above clinical features.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.55 ERCC1 Eleanor Williams Classified gene: ERCC1 as Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.55 ERCC1 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green for now, but with recommendation for amber or red rating at the next GMS review. There does not appear to be evidence that this is a white matter disorder.
White matter disorders and cerebral calcification - childhood onset v1.55 ERCC1 Eleanor Williams Gene: ercc1 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.54 ERCC1 Eleanor Williams Publications for gene: ERCC1 were set to 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure; 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome
White matter disorders and cerebral calcification - childhood onset v1.53 ERCC1 Eleanor Williams edited their review of gene: ERCC1: Added comment: 3 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - can't access paper. Not in PubMed but review by Gregg et al 2011 (PMID: 21612988) report that it describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.; Changed rating: AMBER; Changed publications: 17273966, 23623389, 21612988; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.53 ERCC1 Eleanor Williams Added comment: Comment on phenotypes: Only associated with Cerebrooculofacioskeletal syndrome 4 in OMIM and Gene2Phenotype so removing Xeroderma pigmentosum as a phenotype.
White matter disorders and cerebral calcification - childhood onset v1.53 ERCC1 Eleanor Williams Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosum to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Cerebral vascular malformations v2.47 SETD5 Sarah Leigh Classified gene: SETD5 as Red List (low evidence)
Cerebral vascular malformations v2.47 SETD5 Sarah Leigh Added comment: Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761.
Cerebral vascular malformations v2.47 SETD5 Sarah Leigh Gene: setd5 has been classified as Red List (Low Evidence).
Cerebral vascular malformations v2.46 SETD5 Sarah Leigh Phenotypes for gene: SETD5 were changed from MoyaMoya; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336 to Moyamoya disease MONDO:0016820; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336
Cerebral vascular malformations v2.45 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946 to Moyamoya disease MONDO:0016820; Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Cerebral vascular malformations v2.44 CHD4 Sarah Leigh changed review comment from: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene / condition association. Moya Moya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.; to: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moyamoya disease MONDO:0016820, this is a new gene / condition association. Moyamoya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moyamoya.
Cerebral vascular malformations v2.44 CNOT3 Sarah Leigh Phenotypes for gene: CNOT3 were changed from Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864 to Moyamoya disease MONDO:0016820; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864
Cerebral vascular malformations v2.43 CNOT3 Sarah Leigh changed review comment from: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), who also had some of the features of OMIM:618672.; to: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya disease MONDO:0016820, who also had some of the features of OMIM:618672.
White matter disorders and cerebral calcification - childhood onset v1.52 EPRS Eleanor Williams Classified gene: EPRS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.52 EPRS Eleanor Williams Gene: eprs has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.51 EPRS Eleanor Williams Tag Q2_21_rating tag was added to gene: EPRS.
White matter disorders and cerebral calcification - childhood onset v1.51 EPRS Eleanor Williams Classified gene: EPRS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.51 EPRS Eleanor Williams Added comment: Comment on list classification: promoting from grey to amber but with recommendation for green rating following GMS review. 4 unrelated cases, presentation before age of 18.
White matter disorders and cerebral calcification - childhood onset v1.51 EPRS Eleanor Williams Gene: eprs has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.43 SETD5 Sarah Leigh Phenotypes for gene: SETD5 were changed from Moya Moya; Mental retardation, autosomal dominant 23, MIM# 615761 to MoyaMoya; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336
Early onset or syndromic epilepsy v2.330 UFSP2 Tracy Lester gene: UFSP2 was added
gene: UFSP2 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Penetrance for gene: UFSP2 were set to Complete
Mode of pathogenicity for gene: UFSP2 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: UFSP2 was set to GREEN
Added comment: This is a founder variant that has been reported homozygously in several individuals with an epileptic encephalopathy like phenotype. Three additional cases have been identified in the GEL 100K database by the MSK GeCIP. Recessive LOF variants in this gene cause a skeletal dysplasia phenotype. Functional studies support a gain of function for this variant.
Sources: NHS GMS
White matter disorders and cerebral calcification - childhood onset v1.50 EPRS Eleanor Williams edited their review of gene: EPRS: Added comment: As reported by the expert reviewer PMID: 29576217 (Mendes et al 2018) reports 4 unrelated affected individuals with hypomyelination and biallelic (homozygous or compound het) pathogenic variants in EPRS. 5 variants in total identified (1 nonsense, 1 frameshift, 3 missense). Variants segregated with the disease in all 4 families. All 4 presented initially before the age of 18 and in all brain MRI showed a hypomyelinating leukodystrophy with thinning of the corpus callosum. In 3 cases the variant was identified by WES, in one by direct sequencing of EPRS1.

PMID: 33805425 - Sawaguchi et al 2021 - using a mouse model they show that EPRS1 variant Arg339-to-Ter (R339X) (found in one of the patients in Mendes et al in heterozgyous state with another variant) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells. Wild-type proteins are distributed throughout the cell bodies. This seems to inhibit cell morphological differentiation.; Changed rating: GREEN; Changed publications: 29576217, 33805425; Changed phenotypes: Leukodystrophy, hypomyelinating, 15, OMIM:617951; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh changed review comment from: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672 in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), in addition to some of the features of OMIM:618672.; to: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), who also had some of the features of OMIM:618672.
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh Classified gene: CNOT3 as Amber List (moderate evidence)
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh Added comment: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672 in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), in addition to some of the features of OMIM:618672.
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh Gene: cnot3 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.41 CNOT3 Sarah Leigh Phenotypes for gene: CNOT3 were changed from Moya Moya; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM# 618672 to Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864
Leukodystrophy, adult onset v1.8 EPRS Eleanor Williams commented on gene: EPRS
Leukodystrophy, adult onset v1.8 EPRS Eleanor Williams Tag new-gene-name tag was added to gene: EPRS.
White matter disorders and cerebral calcification - childhood onset v1.50 EPRS Eleanor Williams commented on gene: EPRS
White matter disorders and cerebral calcification - childhood onset v1.50 EPRS Eleanor Williams Tag new-gene-name tag was added to gene: EPRS.
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh changed review comment from: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene condition association. Moya Moya is relevant to this panel -Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.; to: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene / condition association. Moya Moya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh Classified gene: CHD4 as Red List (low evidence)
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh Added comment: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene condition association. Moya Moya is relevant to this panel -Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh Gene: chd4 has been classified as Red List (Low Evidence).
Cerebral vascular malformations v2.39 CHD4 Sarah Leigh Publications for gene: CHD4 were set to 31474762; 27616479
Cerebral vascular malformations v2.38 CHD4 Sarah Leigh Publications for gene: CHD4 were set to 31474762
Fetal anomalies v1.644 CHD4 Sarah Leigh Added comment: Comment on phenotypes: Syndromic INTELLECTUAL DISABILITY with or without congenital heart disease
Fetal anomalies v1.644 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Syndromic INTELLECTUAL DISABILITY with or without congenital heart disease to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Intellectual disability v3.1042 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome 617159 to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Cerebral vascular malformations v2.37 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Moya Moya; Sifrim-Hitz-Weiss syndrome, MIM# 617159 to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Arthrogryposis v3.98 ERBB3 Sarah Leigh edited their review of gene: ERBB3: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Lethal congenital contractural syndrome 2 OMIM:607598 and as a confirmed gene for Hirschprung disease with intestinal pseudo-obstruction. At least 7 variants reported in at least 4 unrelated cases.; Changed rating: GREEN
Arthrogryposis v3.98 ERBB3 Sarah Leigh Tag Q2_21_rating tag was added to gene: ERBB3.
Arthrogryposis v3.98 ERBB3 Sarah Leigh Classified gene: ERBB3 as Amber List (moderate evidence)
Arthrogryposis v3.98 ERBB3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Arthrogryposis v3.98 ERBB3 Sarah Leigh Gene: erbb3 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.97 ERBB3 Sarah Leigh Publications for gene: ERBB3 were set to 17701904; 12519750
Arthrogryposis v3.96 ERBB3 Sarah Leigh Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2 607598 to ?Lethal congenital contractural syndrome 2 OMIM:607598; lethal congenital contracture syndrome 2 MONDO:0011868
Skeletal dysplasia v2.91 FBN2 Sarah Leigh Deleted their comment
Skeletal dysplasia v2.91 FBN2 Sarah Leigh commented on gene: FBN2: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.
DDG2P v2.27 FBN2 Sarah Leigh commented on gene: FBN2: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.
DDG2P v2.27 FBN2 Sarah Leigh reviewed gene: FBN2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.643 FBN2 Sarah Leigh reviewed gene: FBN2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.91 FBN2 Sarah Leigh edited their review of gene: FBN2: Added comment: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.91 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
DDG2P v2.27 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from CONGENITAL CONTRACTURAL ARACHNODACTYLY 121050 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Fetal anomalies v1.643 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from CONGENITAL CONTRACTURAL ARACHNODACTYLY to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Skeletal dysplasia v2.90 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital 121050 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Skeletal dysplasia v2.89 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 7493032; 33571691; 25558065; 28383543
DDG2P v2.26 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 10797416; 11281275; 9199560; 8900230; 9737771; 20799338; 9106527
DDG2P v2.25 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Fetal anomalies v1.642 FBN2 Sarah Leigh Publications for gene: FBN2 were set to
Skeletal dysplasia v2.88 FBN2 Sarah Leigh Publications for gene: FBN2 were set to
Fetal anomalies v1.641 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Skeletal dysplasia v2.87 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Arthrogryposis v3.95 FBN2 Sarah Leigh reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Arthrogryposis v3.95 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 7493032; 33571691
Arthrogryposis v3.94 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Arthrogryposis v3.94 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital 121050 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Arthrogryposis v3.93 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 7493032
Likely inborn error of metabolism v2.127 OPA1 Sarah Leigh Added comment: Comment on phenotypes: Optic atrophy plus syndrome, 125250;{Glaucoma, normal tension, susceptibility to}, 606657;Disorders of mitochondrial DNA maintenance and integrity;Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions;Optic atrophy 1, 165500;Mitochondrial DNA Depletion Syndrome;Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Likely inborn error of metabolism v2.127 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to}, 606657; Disorders of mitochondrial DNA maintenance and integrity; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500; Mitochondrial DNA Depletion Syndrome; Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Mitochondrial disorders v2.34 OPA1 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity;{Glaucoma, normal tension, susceptibility to}, 606657
Mitochondrial disorders v2.34 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Disorders of mitochondrial DNA maintenance and integrity; Optic atrophy 1, 165500; {Glaucoma, normal tension, susceptibility to}, 606657; Optic atrophy plus syndrome, 125250; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500 to ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Ataxia and cerebellar anomalies - childhood onset v2.149 OPA1 Sarah Leigh edited their review of gene: OPA1: Added comment: Associated with relevant phenotypes in OMIM and as confirmed Gen2Phen gene for Optic atrophy plus syndrome OMIM:125250 and a probable gene for Behr syndrome OMIM:210000. At least biallelic 11 variants reported in at least 10 unrelated cases (summarized in PMID 28494813, additional file 7).; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.149 OPA1 Sarah Leigh Tag Q2_21_rating tag was added to gene: OPA1.
Ataxia and cerebellar anomalies - childhood onset v2.149 OPA1 Sarah Leigh Classified gene: OPA1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.149 OPA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.149 OPA1 Sarah Leigh Gene: opa1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.148 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome, MIM# 125250 to Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Ataxia and cerebellar anomalies - childhood onset v2.147 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 28494813; 27150940; 24970096; 11017079; 11017080; 17722006; 25012220
Likely inborn error of metabolism v2.126 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 27604308
Mitochondrial disorders v2.33 OPA1 Sarah Leigh Publications for gene: OPA1 were set to
Ataxia and cerebellar anomalies - childhood onset v2.146 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 28494813
Ataxia and cerebellar anomalies - childhood onset v2.145 OPA1 Sarah Leigh Mode of inheritance for gene: OPA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Holoprosencephaly v2.17 DISP1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: DISP1.
Holoprosencephaly v2.17 DISP1 Sarah Leigh Publications for gene: DISP1 were set to 27363716
White matter disorders and cerebral calcification - childhood onset v1.50 DEGS1 Eleanor Williams Classified gene: DEGS1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.50 DEGS1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating at the next GMS review. >3 cases reported with a plausible disease causing variant in DEGS1. Presentation is in young children.
White matter disorders and cerebral calcification - childhood onset v1.50 DEGS1 Eleanor Williams Gene: degs1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.49 DEGS1 Eleanor Williams Tag Q2_21_rating tag was added to gene: DEGS1.
White matter disorders and cerebral calcification - childhood onset v1.49 DEGS1 Eleanor Williams Phenotypes for gene: DEGS1 were changed from Leukodystrophy, hypomyelinating, 18, MIM#618404 to Leukodystrophy, hypomyelinating, 18, OMIM:618404
White matter disorders and cerebral calcification - childhood onset v1.48 DEGS1 Eleanor Williams Publications for gene: DEGS1 were set to 30620338; 30620337
White matter disorders and cerebral calcification - childhood onset v1.47 DEGS1 Eleanor Williams reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30620338, 30620337, 31186544; Phenotypes: Leukodystrophy, hypomyelinating, 18, OMIM:618404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.641 FKBP8 Rhiannon Mellis reviewed gene: FKBP8: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29261186; Phenotypes: Vertebral segmentation defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.144 OPA1 Sarah Leigh Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.143 NKX2-1 Sarah Leigh edited their review of gene: NKX2-1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in unrelated cases of Choreoathetosis, hypothyroidism, and neonatal respiratory distress OMIM:610978.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.143 NKX2-1 Sarah Leigh Tag Q2_21_rating tag was added to gene: NKX2-1.
Ataxia and cerebellar anomalies - childhood onset v2.143 NKX2-1 Sarah Leigh Classified gene: NKX2-1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.143 NKX2-1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.143 NKX2-1 Sarah Leigh Gene: nkx2-1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.47 DCAF17 Eleanor Williams Phenotypes for gene: DCAF17 were changed from Woodhouse-Sakati syndrome, MIM# 241080 to Woodhouse-Sakati syndrome, OMIM:241080
White matter disorders and cerebral calcification - childhood onset v1.46 DCAF17 Eleanor Williams Publications for gene: DCAF17 were set to 19026396; 20507343
White matter disorders and cerebral calcification - childhood onset v1.45 DCAF17 Eleanor Williams changed review comment from: Associated with Woodhouse-Sakati syndrome in OMIM (#241080 (AR))
DCAF17 is also known as C2ORF37

PMID: 19026396 - Alazami et al 2008 - report single bp deletion in C2orf37 in 8 families of Saudi origin (identified as a founder mutation). Patients phenotypes included hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (Woodhouse-Sakati syndrome). 3 other variants were then found in patients of different ethnicities (another 1 bp deletion leading to a frameshift and 2 variants affecting splice donor sites). The variants segregated with the disease in all families. The two 1 bp changes are predicted to affect the beta isoform only.

PMID: 20507343 - Alazami et al 2010 - report 7 new patients from 4 families (3 ethnic backgrounds, Italian, French Gypsy and Turkish) who present with Woodhouse-Sakati syndrome. Each family had a different variant in C2orf37 - 3 nonsense mutations and a splice site ablation.

PMID: 30409855 - Abusrair et al 2018 - reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome. All participants had confirmed homozygous pathogenic variants in DCAF17. White matter lesions were observed in 18 patients (69.2%).; to: Associated with Woodhouse-Sakati syndrome in OMIM (#241080 (AR))
DCAF17 is also known as C2ORF37

PMID: 19026396 - Alazami et al 2008 - report single bp deletion in C2orf37 in 8 families of Saudi origin (identified as a founder mutation). Patients phenotypes included hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (Woodhouse-Sakati syndrome). 3 other variants were then found in patients of different ethnicities (another 1 bp deletion leading to a frameshift and 2 variants affecting splice donor sites). The variants segregated with the disease in all families. The two 1 bp changes are predicted to affect the beta isoform only.

PMID: 20507343 - Alazami et al 2010 - report 7 new patients from 4 families (3 ethnic backgrounds, Italian, French Gypsy and Turkish) who present with Woodhouse-Sakati syndrome. Each family had a different variant in C2orf37 - 3 nonsense mutations and a splice site ablation.

PMID: 30409855 - Abusrair et al 2018 - reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome. All participants had confirmed homozygous pathogenic variants in DCAF17. White matter lesions were observed in 18 patients (69.2%).

PMID: 31726291 - Bohlega et al 2019 - report on 38 individuals from 17 families were identified as having a clinically and genetically confirmed diagnosis of WSS. All patients shared the same founder DCAF17: NM_001164821:exon4: c.436delC:p.L146fs frameshift deletion. Two groups identified based on phenotype. The age of onset of neurological symptoms for the group with the more severe phenotype was 12.6 ± 4.5 years (range, 9–17 years).
Ataxia and cerebellar anomalies - childhood onset v2.142 NKX2-1 Sarah Leigh Phenotypes for gene: NKX2-1 were changed from Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700 to Choreoathetosis, hypothyroidism, and neonatal respiratory distress OMIM; hereditary progressive chorea without dementia MONDO:0021011:610978; brain-lung-thyroid syndrome MONDO:0012593; Chorea, hereditary benign OMIM:118700
Ataxia and cerebellar anomalies - childhood onset v2.141 MVK Sarah Leigh edited their review of gene: MVK: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Mevalonic aciduria OMIM:610377. At least nine variants reported at least seven unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.141 MVK Sarah Leigh Tag Q2_21_rating tag was added to gene: MVK.
White matter disorders and cerebral calcification - childhood onset v1.45 DCAF17 Eleanor Williams Classified gene: DCAF17 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.45 DCAF17 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for green rating following GMS review. >3 cases of variants in DCAF17 in patients with Woodhouse-Sakati syndrome and white matter lesions observed in approx 70% of patients.
White matter disorders and cerebral calcification - childhood onset v1.45 DCAF17 Eleanor Williams Gene: dcaf17 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.44 DCAF17 Eleanor Williams Tag Q2_21_rating tag was added to gene: DCAF17.
Ataxia and cerebellar anomalies - childhood onset v2.141 MVK Sarah Leigh Publications for gene: MVK were set to 24896178; 26503795
Ataxia and cerebellar anomalies - childhood onset v2.140 MVK Sarah Leigh Added comment: Comment on phenotypes: Variants are associated with Hyper-IgD syndrome OMIM:260920 (biallelic) & Porokeratosis 3, multiple types OMIM:175900 (monoallelic).
Ataxia and cerebellar anomalies - childhood onset v2.140 MVK Sarah Leigh Phenotypes for gene: MVK were changed from Mevalonic aciduria 610377 to Mevalonic aciduria OMIM:610377; mevalonic aciduria MONDO:0012481
White matter disorders and cerebral calcification - childhood onset v1.44 DCAF17 Eleanor Williams reviewed gene: DCAF17: Rating: ; Mode of pathogenicity: None; Publications: 19026396, 20507343, 30409855; Phenotypes: Woodhouse-Sakati syndrome OMIM:241080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.139 MTFMT Sarah Leigh edited their review of gene: MTFMT: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least eight variants reported in at least eight unrelated cases of Combined oxidative phosphorylation deficiency 15 OMIM:614947.; Changed rating: GREEN
Intellectual disability v3.1041 PIGC Arina Puzriakova Classified gene: PIGC as Amber List (moderate evidence)
Intellectual disability v3.1041 PIGC Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated families with biallelic variants in this gene, and severe DD/ID is evident in all cases (PMIDs: 27694521; 32707268) . Therefore, PIGC can be upgraded to Green status at the next GMS panel update.
Intellectual disability v3.1041 PIGC Arina Puzriakova Gene: pigc has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.139 MTFMT Sarah Leigh Tag Q2_21_rating tag was added to gene: MTFMT.
Ataxia and cerebellar anomalies - childhood onset v2.139 MTFMT Sarah Leigh Classified gene: MTFMT as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.139 MTFMT Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.139 MTFMT Sarah Leigh Gene: mtfmt has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.138 MTFMT Sarah Leigh Publications for gene: MTFMT were set to 26060307; 24461907
Intellectual disability v3.1040 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Intellectual disability v3.1039 PIGC Arina Puzriakova Publications for gene: PIGC were set to 27694521
Ataxia and cerebellar anomalies - childhood onset v2.137 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15 MIM#614947; Mitochondrial complex I deficiency, nuclear type 27 MIM#618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Intellectual disability v3.1038 PIGC Arina Puzriakova Tag Q2_21_rating tag was added to gene: PIGC.
Mitochondrial disorders v2.32 MTFMT Sarah Leigh Added comment: Comment on phenotypes: Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Mitochondrial disorders v2.32 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 15, 614947; Mitochondrial complex I deficiency, nuclear type 27 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Early onset or syndromic epilepsy v2.330 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Early onset or syndromic epilepsy v2.329 PIGC Arina Puzriakova Publications for gene: PIGC were set to
Early onset or syndromic epilepsy v2.328 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1038 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.91 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947; Mitochondrial complex I deficiency, nuclear type 27, 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Intellectual disability v3.1038 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Likely inborn error of metabolism v2.125 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15 614947; Mitochondrial complex I deficiency, nuclear type 27 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Possible mitochondrial disorder, nuclear genes v1.41 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947; Mitochondrial complex I deficiency, nuclear type 27, 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Inherited white matter disorders v1.91 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15; 614947; 22499348; 23499752 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 MPEG1 Arina Puzriakova Phenotypes for gene: MPEG1 were changed from Immunodeficiency 77, MIM# 619223 to Immunodeficiency 77, OMIM:619223
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Classified gene: MPEG1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient number of unrelated cases (5 - PMIDs: 33224153; 28422754) with immunopathology and distinct biallelic variants in this gene to rate as Green at the next GMS panel update. Supported by functional evidence and animal model.

MPEG1 is also associated with a relevant phenotype in OMIM (MIM# 619223)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Gene: mpeg1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 MPEG1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MPEG1.
Intestinal failure or congenital diarrhoea v1.36 IL37 Arina Puzriakova gene: IL37 was added
gene: IL37 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 IL37 Arina Puzriakova Classified gene: IL37 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 IL37 Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence, as only a single case reported to date (PMID: 33674380)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 IL37 Arina Puzriakova Gene: il37 has been classified as Red List (Low Evidence).
Hereditary spastic paraplegia, adult onset v1.17 CYP2U1 Sarah Leigh changed review comment from: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of CYP2U1 on the this - Hereditary spastic paraplegia - adult onset, as variants in CYP2U1 are usually associated with Spastic paraplegia 56, autosomal recessive OMIM:615030 in childhood. The green rating may be justified to ensure that edge cases may be identified.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of CYP2U1 on the Hereditary spastic paraplegia - adult onset panel, as variants in CYP2U1 are usually associated with Spastic paraplegia 56, autosomal recessive OMIM:615030 in childhood. The green rating may be justified to ensure that edge cases may be identified.
GMS opinion is sort on this issue.
Hereditary spastic paraplegia, adult onset v1.17 CYP2U1 Sarah Leigh reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.17 CYP2U1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CYP2U1.
Ataxia and cerebellar anomalies - childhood onset v2.136 ADPRHL2 Sarah Leigh Tag Q2_21_rating tag was added to gene: ADPRHL2.
Hereditary ataxia, adult onset v2.42 ADPRHL2 Sarah Leigh changed review comment from: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood. The green rating may be justifyied inorder to ensure that edge cases may be identified.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood. The green rating may be justified to ensure that edge cases may be identified.
GMS opinion is sort on this issue.
Hereditary ataxia, adult onset v2.42 ADPRHL2 Sarah Leigh changed review comment from: The Q2_21_expert_review has been added to this gene as there is a conflict of opinion of the rating of this ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood. The green rating may be justifyied inorder to ensure that edge cases may be identified.
GMS opinion is sort on this issue.
Hereditary ataxia, adult onset v2.42 ADPRHL2 Sarah Leigh changed review comment from: The Q2_21_expert_review has been added to this gene as there is a conflict of opinion of the rating of this ADPRHL2 on the this - Hereditary ataxia - adult onset - panel.as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review has been added to this gene as there is a conflict of opinion of the rating of this ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood.
GMS opinion is sort on this issue.
Hereditary ataxia, adult onset v2.42 ADPRHL2 Sarah Leigh reviewed gene: ADPRHL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.42 ADPRHL2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: ADPRHL2.
Ataxia and cerebellar anomalies - childhood onset v2.136 EEF2 Eleanor Williams Classified gene: EEF2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.136 EEF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber on advice of Genomics England clinical team. Amber rating selected pending further cases and delineation of the phenotype
Ataxia and cerebellar anomalies - childhood onset v2.136 EEF2 Eleanor Williams Gene: eef2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.135 EEF2 Eleanor Williams gene: EEF2 was added
gene: EEF2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: EEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EEF2 were set to 23001565; 33355653
Phenotypes for gene: EEF2 were set to Spinocerebellar ataxia 26 OMIM:609306
Review for gene: EEF2 was set to AMBER
Added comment: Provisionally associated with ?Spinocerebellar ataxia 26 #609306 (AD) in OMIM based on Hekman et al 2012 case.

PMID: 23001565 - Hekman et al 2012 - report a six-generation kindred of Norwegian ancestry with a late-onset pure cerebellar ataxia in which a heterozygous P596H substitution in eEF2 was found to segregate with the disease phenotype in 24 individuals and two currently asymptomatic individuals. Functional studies in yeast showed that the variant (P580H in the EFT2 gene in yeast) affected translational fidelity.

PMID: 33355653 - Nabais Sá et al 2021 - identified de novo EEF2 missense variants in 3 unrelated children (3, 6 and 9 years of age) with a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly.
Sources: Literature
Hereditary ataxia, adult onset v2.42 EEF2 Eleanor Williams Classified gene: EEF2 as Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.42 EEF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber on advice of Genomics England clinical team. Amber rating selected pending further cases and delineation of the phenotype
Hereditary ataxia, adult onset v2.42 EEF2 Eleanor Williams Gene: eef2 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.41 EEF2 Eleanor Williams gene: EEF2 was added
gene: EEF2 was added to Hereditary ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: EEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EEF2 were set to 23001565; 33355653
Phenotypes for gene: EEF2 were set to Spinocerebellar ataxia 26 OMIM:609306
Review for gene: EEF2 was set to AMBER
Added comment: Provisionally associated with ?Spinocerebellar ataxia 26 #609306 (AD) in OMIM based on Hekman et al 2012 case.

PMID: 23001565 - Hekman et al 2012 - report a six-generation kindred of Norwegian ancestry with a late-onset pure cerebellar ataxia in which a heterozygous P596H substitution in eEF2 was found to segregate with the disease phenotype in 24 individuals and two currently asymptomatic individuals. Functional studies in yeast showed that the variant (P580H in the EFT2 gene in yeast) affected translational fidelity.

PMID: 33355653 - Nabais Sá et al 2021 - identified de novo EEF2 missense variants in 3 unrelated children (3, 6 and 9 years of age) with a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly.
Sources: Literature
Severe insulin resistance and lipodystrophy syndromes v2.9 OTULIN Zornitza Stark gene: OTULIN was added
gene: OTULIN was added to Lipodystrophy - childhood onset. Sources: Expert Review
Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTULIN were set to 27523608; 27559085
Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Review for gene: OTULIN was set to GREEN
gene: OTULIN was marked as current diagnostic
Added comment: Autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein, leukocytosis, and neutrophilia in the absence of any infection.

At least 3 unrelated families reported.
Sources: Expert Review
Severe insulin resistance and lipodystrophy syndromes v2.9 KCNJ6 Zornitza Stark gene: KCNJ6 was added
gene: KCNJ6 was added to Lipodystrophy - childhood onset. Sources: Expert Review
Mode of inheritance for gene: KCNJ6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ6 were set to 25620207; 29852244
Phenotypes for gene: KCNJ6 were set to Keppen-Lubinsky syndrome, MIM# 614098; MONDO:0013572
Review for gene: KCNJ6 was set to GREEN
gene: KCNJ6 was marked as current diagnostic
Added comment: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.
Sources: Expert Review
Severe insulin resistance and lipodystrophy syndromes v2.9 FBN1 Zornitza Stark gene: FBN1 was added
gene: FBN1 was added to Lipodystrophy - childhood onset. Sources: Expert Review
Mode of inheritance for gene: FBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBN1 were set to 20979188; 21594992; 21594993; 24613577; 26860060; 29666143
Phenotypes for gene: FBN1 were set to Marfan lipodystrophy syndrome, MIM# 616914
Review for gene: FBN1 was set to GREEN
gene: FBN1 was marked as current diagnostic
Added comment: The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development.

This specific phenotype is caused by variants occurring in or affecting exon 64.

More than 5 unrelated individuals reported, rabbit model.
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Classified gene: ZNFX1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (10 - PMIDs: 33876776; 33872655) with immunopathology and biallelic variants in this gene to rate as Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Gene: znfx1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.415 ZNFX1 Arina Puzriakova Publications for gene: ZNFX1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 ZNFX1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ZNFX1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 ZNFX1 Arina Puzriakova reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33876776, 33872655; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.134 CYP2U1 Sarah Leigh changed review comment from: Comment on phenotypes: Autosomal recessive spastic paraplegia 56 (#615030) complex form of disorder, ataxia not yet identified in affected patients.; to: Comment on phenotypes: Autosomal recessive spastic paraplegia 56 (#615030) is a complex form of disorder, ataxia not yet identified in affected patients (Table 1 in PMID: 27292318 provides a review of cases reported so far).
Ataxia and cerebellar anomalies - childhood onset v2.134 CYP2U1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CYP2U1.
Intellectual disability v3.1037 JMJD1C Zornitza Stark gene: JMJD1C was added
gene: JMJD1C was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Review for gene: JMJD1C was set to GREEN
gene: JMJD1C was marked as current diagnostic
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity.

Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679).

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Tag Q2_21_rating tag was added to gene: SYK.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Classified gene: SYK as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - PMID:33782605 report distinct monoallelic GoF variants in 5 families (6 individuals) with immune dysregulation and inflammation. Expression of one of these variants in a mouse model replicated aspects of the human immunopathology.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Gene: syk has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.16 DISP1 Zornitza Stark reviewed gene: DISP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19184110, 26748417, 23542665; Phenotypes: Holoprosencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haematological malignancies for rare disease v1.1 RAD51 Zornitza Stark reviewed gene: RAD51: Rating: GREEN; Mode of pathogenicity: None; Publications: 30907510; Phenotypes: Fanconi anemia, complementation group R 617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare multisystem ciliopathy disorders v1.142 LAMA1 Sarah Leigh reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1037 LAMA1 Sarah Leigh reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.134 LAMA1 Sarah Leigh edited their review of gene: LAMA1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in at least three unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.134 LAMA1 Sarah Leigh Tag Q2_21_rating tag was added to gene: LAMA1.
Intellectual disability v3.1037 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Rare multisystem ciliopathy disorders v1.142 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from cerebellar cysts; myopia; cerebellar vermis hypoplasia; gaze palsy; retinitis pigments to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Intellectual disability v3.1036 LAMA1 Sarah Leigh Publications for gene: LAMA1 were set to 21937992; 30244536
Rare multisystem ciliopathy disorders v1.141 LAMA1 Sarah Leigh Publications for gene: LAMA1 were set to https://www.ncbi.nlm.nih.gov/pubmed/25105227
Rare multisystem ciliopathy disorders v1.140 LAMA1 Sarah Leigh Classified gene: LAMA1 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.140 LAMA1 Sarah Leigh Gene: lama1 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.134 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from Cerebellar ataxia, intellectual disability, oculomotor apraxia, cerebellar cysts; Poretti Boltshauser syndrome MIM#615960 to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Ataxia and cerebellar anomalies - childhood onset v2.133 LAMA1 Sarah Leigh Classified gene: LAMA1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.133 LAMA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.133 LAMA1 Sarah Leigh Gene: lama1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.132 KCNA2 Sarah Leigh edited their review of gene: KCNA2: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported in numberous cases, together with supportive functional studies, demonstrating GOF and LOF mechanisms.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.132 KCNA2 Sarah Leigh Classified gene: KCNA2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.132 KCNA2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.132 KCNA2 Sarah Leigh Gene: kcna2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.131 KCNA2 Sarah Leigh Tag Q2_21_rating tag was added to gene: KCNA2.
Ataxia and cerebellar anomalies - childhood onset v2.131 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 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
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both dominant negative variants that result in LOF effect (RCV000170511, rs786205231) and GOF variants (rs786205231, rs786205232) have been associated with Developmental and epileptic encephalopathy 32 OMIM:616366
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 was changed from None to None
Hereditary ataxia v1.216 EEF2 Eleanor Williams Classified gene: EEF2 as Amber List (moderate evidence)
Hereditary ataxia v1.216 EEF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber on advice of Genomics England clinical team. Amber rating selected pending further cases and delineation of the phenotype
Hereditary ataxia v1.216 EEF2 Eleanor Williams Gene: eef2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.327 KCNA2 Sarah Leigh Phenotypes for gene: KCNA2 were changed from Epileptic encephalopathy, early infantile, 32; EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 32 OMIM:616366; developmental and epileptic encephalopathy, 32 MONDO:0014607
Ataxia and cerebellar anomalies - childhood onset v2.130 KCNA2 Sarah Leigh Phenotypes for gene: KCNA2 were changed from Early infantile encephalopathy 32, MIM#616366 to Developmental and epileptic encephalopathy 32 OMIM:616366; developmental and epileptic encephalopathy, 32 MONDO:0014607
Ataxia and cerebellar anomalies - childhood onset v2.129 KCNA2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both dominant negative variants that result in LOF effect (RCV000170511, rs786205231) and GOF variants (rs786205231, rs786205232) have been associated with Developmental and epileptic encephalopathy 32 OMIM:616366
Ataxia and cerebellar anomalies - childhood onset v2.129 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 was changed from None to None
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene as Green at the next GMS panel update - sufficient number of unrelated cases (4, plus 1 unpublished), all presenting GDD as an early feature. Particularly pertinent to less severely affected individuals who do not develop seizures.
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.326 KCNA2 Sarah Leigh Publications for gene: KCNA2 were set to Syrbe et al (2015) Nat Genet 47(4): 393-9
Ataxia and cerebellar anomalies - childhood onset v2.128 KCNA2 Sarah Leigh Publications for gene: KCNA2 were set to 29050392
Intellectual disability v3.1034 NEUROD2 Arina Puzriakova gene: NEUROD2 was added
gene: NEUROD2 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: NEUROD2.
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 16504944; 30323019; 33438828
Phenotypes for gene: NEUROD2 were set to Developmental and epileptic encephalopathy 72, OMIM:618374
Review for gene: NEUROD2 was set to GREEN
Added comment: NEUROD2 is associated with a relevant phenotype in OMIM (MIM# 618374), but is not yet listed in Gene2Phenotype.

- PMID: 30323019 (2019) - Two unrelated children with refractory early-infantile epileptic encephalopathy. Developmental delay (DD) preceded onset of seizures in both cases, with signs of DD becoming evident at 2-4 months and seizures arising at 5 months of age. Patient 1 became seizure-free after introducing a ketogenic diet at 16 months; however, an EEG at 22 months remained abnormal and she continues to have severe GDD with no independent sitting, walking or speaking at the chronological age of 3 years and 2 months. Patient 2 became seizure-free when a vagal nerve stimulator (VNS) was placed at 16 months of age. He displayed significant improvement on EEG and subsequently began regaining neurodevelopmental milestones.
WES revealed different de novo variants in the NEUROD2 gene (P1: c.388G>C, p.E130Q; P2: c.401T>C, p.M134T, respectively). Knockdown of the neurod2 in Xenopus tropicalis tadpoles resulted in abnormal swimming behaviour and progressive seizures followed by periods of immobility. Overexpression of wild-type human NEUROD2 in tadpoles induced non-neuronal cells to differentiate into neurons - on the other hand, overexpression of the mutant alleles failed to to cause any (p.E130Q) or a comparable degree (p.M134T) of ectopic neuronal induction as seen with the wild-type protein.

- Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word)

----- Cases without seizures -

- PMID: 33438828 (2021) - Adolescent (14 yrs old) with GDD but without seizures who was found to have a novel de novo NEUROD2 missense variant (c.488 T > C, p.L163P). An additional individual (12 yrs) with DD and a different missense NEUROD2 (c.703G>A, p.A235T) was also identified, but lacking parental samples for segregation analysis.
Functional analysis in Xenopus laevis revealed that injection of the p.L163P mRNA variant resulted in a defective ability to induce ectopic neurons in tadpoles as compared with wild-type NEUROD2 mRNA, while the p.A235T variant functioned similarly to wild-type.
Sources: Literature
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NEUROD2.
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Added comment: - Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word); Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.127 EXOSC1 Sarah Leigh Added comment: Comment on phenotypes: No phenotype in OMIM or in MONDO (21/04/2021)
Ataxia and cerebellar anomalies - childhood onset v2.127 EXOSC1 Sarah Leigh Phenotypes for gene: EXOSC1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia
Ataxia and cerebellar anomalies - childhood onset v2.126 EXOSC1 Sarah Leigh Classified gene: EXOSC1 as Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.126 EXOSC1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic variant reported.
Ataxia and cerebellar anomalies - childhood onset v2.126 EXOSC1 Sarah Leigh Gene: exosc1 has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.125 EXOSC1 Sarah Leigh Added comment: Comment on phenotypes: No phenotype listed in OMIM or in MONDO (21/04/2021)
Ataxia and cerebellar anomalies - childhood onset v2.125 EXOSC1 Sarah Leigh Phenotypes for gene: EXOSC1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia
Ataxia and cerebellar anomalies - childhood onset v2.124 EXOSC1 Sarah Leigh Classified gene: EXOSC1 as Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.124 EXOSC1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic variant reported (PMID 33463720).
Ataxia and cerebellar anomalies - childhood onset v2.124 EXOSC1 Sarah Leigh Gene: exosc1 has been classified as Red List (Low Evidence).
Likely inborn error of metabolism v2.124 NDUFB7 Sarah Leigh Added comment: Comment on phenotypes: No OMIM or MONDO phenotype (21/4/2021)
Likely inborn error of metabolism v2.124 NDUFB7 Sarah Leigh Phenotypes for gene: NDUFB7 were changed from No OMIM phenotype; Isolated complex I deficiency to Congenital lactic acidosis; hypertrophic cardiomyopathy
Mitochondrial disorders v2.31 NDUFB7 Sarah Leigh Added comment: Comment on phenotypes: No OMIM or MONDO phenotype (21/4/2021)
Mitochondrial disorders v2.31 NDUFB7 Sarah Leigh Phenotypes for gene: NDUFB7 were changed from Isolated complex I deficiency; No OMIM phenotype to Congenital lactic acidosis; hypertrophic cardiomyopathy
Likely inborn error of metabolism v2.123 NDUFB7 Sarah Leigh Mode of inheritance for gene: NDUFB7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Tag watchlist tag was added to gene: NDUFB7.
Mitochondrial disorder with complex I deficiency v1.13 NDUFB7 Sarah Leigh Added comment: Comment on phenotypes: No OMIM or MONDO phenotype (21/4/2021)
Mitochondrial disorder with complex I deficiency v1.13 NDUFB7 Sarah Leigh Phenotypes for gene: NDUFB7 were changed from No OMIM phenotype to Congenital lactic acidosis; hypertrophic cardiomyopathy
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Classified gene: NDUFB7 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Added comment: Comment on list classification: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic splicing variant reported. RNA sequencing revealed that this variant disrupted normal splicing (PMID 33502047) and human knock-out cells have shown that NDUFB7 is one of the subunits strictly required for assembly of a functional mitochondrial complex I subunit, which is essential for cell viability (PMID 27626371).
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex I deficiency v1.12 NDUFB7 Sarah Leigh Tag watchlist tag was added to gene: NDUFB7.
Likely inborn error of metabolism v2.121 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to 33502047; 27626371
Mitochondrial disorders v2.30 NDUFB7 Sarah Leigh Tag watchlist tag was added to gene: NDUFB7.
Likely inborn error of metabolism v2.121 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to
Mitochondrial disorder with complex I deficiency v1.12 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to
Mitochondrial disorders v2.30 NDUFB7 Sarah Leigh Mode of inheritance for gene: NDUFB7 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.11 NDUFB7 Sarah Leigh Mode of inheritance for gene: NDUFB7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.10 NDUFB7 Sarah Leigh Classified gene: NDUFB7 as Amber List (moderate evidence)
Mitochondrial disorder with complex I deficiency v1.10 NDUFB7 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic splicing variant reported. RNA sequencing revealed that this variant disrupted normal splicing (PMID 33502047) and human knock-out cells have shown that NDUFB7 is one of the subunits strictly required for assembly of a functional mitochondrial complex I subunit, which is essential for cell viability (PMID 27626371).
Mitochondrial disorder with complex I deficiency v1.10 NDUFB7 Sarah Leigh Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.29 NDUFB7 Sarah Leigh Classified gene: NDUFB7 as Amber List (moderate evidence)
Mitochondrial disorders v2.29 NDUFB7 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic splicing variant reported. RNA sequencing revealed that this variant disrupted normal splicing (PMID 33502047) and human knock-out cells have shown that NDUFB7 is one of the subunits strictly required for assembly of a functional mitochondrial complex I subunit, which is essential for cell viability (PMID 27626371).
Mitochondrial disorders v2.29 NDUFB7 Sarah Leigh Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.28 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to
Clefting v2.28 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Red List (low evidence)
Clefting v2.28 ACBD5 Arina Puzriakova Added comment: Comment on list classification: Only a single patient reported with a cleft palate to date, and therefore rating Red on this panel.
Clefting v2.28 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Red List (Low Evidence).
Clefting v2.27 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from Cleft palate to Retinal dystrophy with leukodystrophy, OMIM:618863
Clefting v2.26 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to
Clefting v2.25 ACBD5 Arina Puzriakova Mode of inheritance for gene: ACBD5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.90 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409, 27899449, 23105016
Inherited white matter disorders v1.89 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from to Retinal dystrophy with leukodystrophy, OMIM:618863
Inherited white matter disorders v1.88 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Green List (high evidence)
Inherited white matter disorders v1.88 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.87 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23105016, 27899449, 27799409, 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.44 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from Retinal dystrophy with leukodystrophy, OMIM:618863 to Retinal dystrophy with leukodystrophy, OMIM:618863
White matter disorders and cerebral calcification - childhood onset v1.43 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 23105016; 27899449; 27799409; 33427402
Peroxisomal disorders v1.12 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409; 23105016; 33427402
White matter disorders and cerebral calcification - childhood onset v1.42 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409, 27899449, 23105016
White matter disorders and cerebral calcification - childhood onset v1.41 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from to Retinal dystrophy with leukodystrophy, OMIM:618863
White matter disorders and cerebral calcification - childhood onset v1.40 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.40 ACBD5 Arina Puzriakova Added comment: Comment on list classification: There is are sufficient unrelated cases (3) to support a diagnostic-grade classification (Green) at the next GMS panel update
White matter disorders and cerebral calcification - childhood onset v1.40 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.39 ACBD5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ACBD5.
White matter disorders and cerebral calcification - childhood onset v1.39 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23105016, 27799409, 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova Tag Q2_21_rating was removed from gene: ACBD5.
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova changed review comment from: Comment on list classification: There is are sufficient unrelated cases (4) to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: There is are sufficient unrelated cases (4) to support a diagnostic-grade classification (Green)
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Green List (high evidence)
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Green List (High Evidence).
Peroxisomal disorders v1.10 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from Retinal dystrophy with leukodystrophy (MIM#618863) to Retinal dystrophy with leukodystrophy, OMIM:618863
Peroxisomal disorders v1.9 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409; 23105016
Peroxisomal disorders v1.8 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Amber List (moderate evidence)
Peroxisomal disorders v1.8 ACBD5 Arina Puzriakova Added comment: Comment on list classification: There is are sufficient unrelated cases (4) to promote this gene to Green at the next GMS panel update.
Peroxisomal disorders v1.8 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Amber List (Moderate Evidence).
Peroxisomal disorders v1.7 ACBD5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ACBD5.
Peroxisomal disorders v1.7 ACBD5 Arina Puzriakova commented on gene: ACBD5: A fourth individual was identified by Dr Helen Brittain (Genomics England Clinical Fellow) who presented with retinal dystrophy, ataxia and developmental regression at 2 yrs old
Peroxisomal disorders v1.7 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.184 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409; 23105016
Retinal disorders v2.183 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Amber List (moderate evidence)
Retinal disorders v2.183 ACBD5 Arina Puzriakova Added comment: Comment on list classification: There is are now sufficient unrelated cases (4) of retinal dystrophy in patients with biallelic ACBD5 variants to promote this gene to Green at the next GMS panel update.
Retinal disorders v2.183 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.182 ACBD5 Arina Puzriakova Tag watchlist was removed from gene: ACBD5.
Tag Q2_21_rating tag was added to gene: ACBD5.
Retinal disorders v2.182 ACBD5 Arina Puzriakova commented on gene: ACBD5: A fourth individual was identified by Dr Helen Brittain (Genomics England Clinical Fellow) who presented with retinal dystrophy, ataxia and developmental regression at 2 yrs old
Retinal disorders v2.182 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.120 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627 to ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627
Likely inborn error of metabolism v2.119 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.119 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.118 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.118 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.117 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 618244 to ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627
Likely inborn error of metabolism v2.117 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh edited their review of gene: NDUFA12: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in five unrelated cases, together with supportive studies. Phenotypic variability was evident in the cases reported (PMID: 21617257; 33715266).; Changed rating: GREEN
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Tag Q2_21_rating tag was added to gene: NDUFA12.
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh edited their review of gene: NDUFA12: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in five unrelated cases, together with supportive studies. Phenotypic variability was evident in the cases reported (PMID: 21617257; 33715266).; Changed rating: GREEN
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.26 NDUFA12 Sarah Leigh Tag Q2_21_rating tag was added to gene: NDUFA12.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 SASH3 Boaz Palterer gene: SASH3 was added
gene: SASH3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SASH3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: SASH3 were set to Combined immunodeficiency; lymphopenia; neutropenia; immunodysregulation; autoimmune cytopenias
Penetrance for gene: SASH3 were set to unknown
Review for gene: SASH3 was set to GREEN
Added comment: Delmonte et al. described three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias.
Functional data: Lentivirus-mediated transfer of SASH3 cDNA in KO Jurkat cells and patient's cell lines restored protein expression and cell proliferation. The KO mouse phenotype is compatible.
https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020008629/475781/SASH3-variants-cause-a-novel-form-of-X-linked?redirectedFrom=fulltext
Sources: Literature
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NCKAP1.
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Classified gene: NCKAP1 as Amber List (moderate evidence)
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Guo et al 2020 (PMID:33157009) describe multiple families with inherited and de novo deleterious NCKAP1 variants. Neurodevelopmental features represent the core phenotypes, including autistic features, psychomotor delays, and ID or learning disabilities (10/16 individuals had a diagnosis of mild to severe ID)
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Gene: nckap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1032 NCKAP1 Arina Puzriakova Phenotypes for gene: NCKAP1 were changed from to Intellectual disability; Autism
Intellectual disability v3.1031 NCKAP1 Arina Puzriakova Publications for gene: NCKAP1 were set to
Intellectual disability v3.1030 NCKAP1 Arina Puzriakova Mode of inheritance for gene: NCKAP1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1029 DPYS Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: DPYS.
Intellectual disability v3.1029 DPYS Arina Puzriakova Publications for gene: DPYS were set to
Intellectual disability v3.1028 DPYS Arina Puzriakova Classified gene: DPYS as Amber List (moderate evidence)
Intellectual disability v3.1028 DPYS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Overall variable clinical presentation, even including asymptomatic subjects. However, DD and/or ID have been reported in multiple published cases (PMIDs: 9266350; 17383919; 20362666; 27604308; 26771602; 29054612). Sufficient unrelated cases (>3) to rate Green but will seek opinion from the GMS expert group due to highly variable penetrance of this phenotype.
Intellectual disability v3.1028 DPYS Arina Puzriakova Gene: dpys has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.26 NDUFA12 Sarah Leigh Added comment: Comment on phenotypes: Isolated complex I deficiency;
Mitochondrial disorders v2.26 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from Isolated complex I deficiency; ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627
Mitochondrial disorders v2.25 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257
White matter disorders and cerebral calcification - childhood onset v1.39 CLDN11 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (entry last edited on 01/14/2013) or Gen2Phen. Two stop loss variants reported in three unrelated cases. Both variants resulted in an 39aa extension - c.622T>C, p.(208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay (PMID 33313762). The reporting authors predict that the extended claudin-11 forms an alpha helix which is not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins.; to: Not associated with relevant phenotype in OMIM (entry last edited on 01/14/2013) or Gen2Phen. Two stop loss variants reported in three unrelated cases. Both variants resulted in an 39aa extension - c.622T>C, p.(208Glnext*39) in two individuals and c.622T>G, p.(208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay (PMID 33313762). The reporting authors predict that the extended claudin-11 forms an alpha helix which is not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins.
White matter disorders and cerebral calcification - childhood onset v1.39 CLDN11 Sarah Leigh edited their review of gene: CLDN11: Added comment: Not associated with relevant phenotype in OMIM (entry last edited on 01/14/2013) or Gen2Phen. Two stop loss variants reported in three unrelated cases. Both variants resulted in an 39aa extension - c.622T>C, p.(208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay (PMID 33313762). The reporting authors predict that the extended claudin-11 forms an alpha helix which is not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins.; Changed rating: GREEN
White matter disorders and cerebral calcification - childhood onset v1.39 CLDN11 Sarah Leigh Tag Q2_21_rating tag was added to gene: CLDN11.
White matter disorders and cerebral calcification - childhood onset v1.39 CLDN11 Sarah Leigh Classified gene: CLDN11 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.39 CLDN11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - childhood onset v1.39 CLDN11 Sarah Leigh Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.182 FAM57B Ivone Leong Phenotypes for gene: FAM57B were changed from Cone-rod dystrophy to Cone-rod dystrophy, MONDO:0015993; Maculopathy
Retinal disorders v2.181 FAM57B Ivone Leong Publications for gene: FAM57B were set to 28041643
Retinal disorders v2.180 FAM57B Ivone Leong Mode of inheritance for gene: FAM57B was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.179 CTNNA1 Ivone Leong Phenotypes for gene: CTNNA1 were changed from Macular dystrophy, patterned, 2, OMIM:608970 to Macular dystrophy, patterned, 2, OMIM:608970; exudative vitreoretinopathy, MONDO:0019516
Retinal disorders v2.178 CTNNA1 Ivone Leong Publications for gene: CTNNA1 were set to 26691986
Likely inborn error of metabolism v2.115 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism) to Dihydropyrimidinuria, OMIM:222748; Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism)
Intellectual disability v3.1027 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinuria, MIM#222748 to Dihydropyrimidinuria, OMIM:222748
Undiagnosed metabolic disorders v1.454 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism) to Dihydropyrimidinuria, OMIM:222748; Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism)
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Tag watchlist tag was added to gene: RHBDF1.
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Classified gene: RHBDF1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.114 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Likely inborn error of metabolism v2.113 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042; Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu, OMIM:615042
Paediatric or syndromic cardiomyopathy v1.36 RHBDF1 Ivone Leong Phenotypes for gene: RHBDF1 were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Congenital muscular dystrophy v2.8 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from musclular dystrophy dystroglycanopathy syndrome with severe epilepsy; Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu, OMIM:615042
Dilated and arrhythmogenic cardiomyopathy v1.22 MYLK3 Ivone Leong Classified gene: MYLK3 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.22 MYLK3 Ivone Leong Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.21 MYLK3 Ivone Leong gene: MYLK3 was added
gene: MYLK3 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Q2_21_rating tags were added to gene: MYLK3.
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709; 30690923
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy, MONDO:0005021
Review for gene: MYLK3 was set to GREEN
Added comment: This gene is also on the Cardiomyopathies - including childhood onset (Version 1.35) as an Amber gene with a recommendation of promoting to Green. This gene is not associated with a phenotype on OMIM or Gene2Phenotype.

PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children.

Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive.

PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM.

PMID: 32870709 describes three consanguineous families with homozygous variants in this gene.

Review from Zornitza Stark:
"Rating: I don't know

Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Created: 16 Apr 2021, 9:24 a.m."

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Arthrogryposis v3.92 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from congenital muscular dystrophies; congenital muscular dystrophies. DPM2-CDG . Musclular dystrophy dystroglycanopathy syndrome with severe epilepsy. to Congenital disorder of glycosylation, type Iu, OMIM:615042
Early onset or syndromic epilepsy v2.324 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042; seizures to Congenital disorder of glycosylation, type Iu, OMIM:615042
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Classified gene: MYLK3 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype on OMIM or Gene2Phenotype.

PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children.

Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive.

PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM.

PMID: 32870709 describes three consanguineous families with homozygous variants in this gene.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.323 DPM2 Arina Puzriakova commented on gene: DPM2
Congenital disorders of glycosylation v2.70 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu, OMIM:615042
Congenital disorders of glycosylation v2.69 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Congenital disorders of glycosylation v2.68 DPM2 Arina Puzriakova Classified gene: DPM2 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.68 DPM2 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 615042). Sufficient number of unrelated cases (3) with DPM2-CDG to rate Green at the next GMS panel update (PMIDs: 23109149; 33129689)
Congenital disorders of glycosylation v2.68 DPM2 Arina Puzriakova Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.34 MYLK3 Ivone Leong Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Paediatric or syndromic cardiomyopathy v1.33 MYLK3 Ivone Leong Tag Q2_21_rating tag was added to gene: MYLK3.
Paediatric or syndromic cardiomyopathy v1.33 MYLK3 Ivone Leong Phenotypes for gene: MYLK3 were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Congenital disorders of glycosylation v2.67 DPM2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM2.
Intellectual disability v3.1026 DPM2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM2.
Intellectual disability v3.1026 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Intellectual disability v3.1025 DPM2 Arina Puzriakova Classified gene: DPM2 as Amber List (moderate evidence)
Intellectual disability v3.1025 DPM2 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 615042). Sufficient number of unrelated cases (3) with DPM2-CDG to rate Green at the next GMS panel update. Phenotypes include intellectual disability in all affected individuals.
Intellectual disability v3.1025 DPM2 Arina Puzriakova Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1024 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu to Congenital disorder of glycosylation, type Iu, OMIM:615042
Paediatric or syndromic cardiomyopathy v1.32 MCM10 Ivone Leong Classified gene: MCM10 as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v1.32 MCM10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. Therefore this gene has been given a Red rating.
Paediatric or syndromic cardiomyopathy v1.32 MCM10 Ivone Leong Gene: mcm10 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v1.31 MCM10 Ivone Leong Phenotypes for gene: MCM10 were changed from Restrictive cardiomyopathy to Restrictive cardiomyopathy, MONDO:0005201
Dilated and arrhythmogenic cardiomyopathy v1.20 NRAP Ivone Leong Publications for gene: NRAP were set to 30384889; 33534821; 28611399; https://doi.org/10.1101/2020.10.12.20211474
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 ZNFX1 Boaz Palterer edited their review of gene: ZNFX1: Added comment: Multisystem Inflammation and Susceptibility to Viral infections in Human ZNFX1 Deficiency
15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic-lymphohistiocytosis-like disease, early-onset seizures, as well as renal and lung disease.
https://www.jacionline.org/article/S0091-6749(21)00613-8/fulltext; Changed rating: GREEN; Changed phenotypes: Multisystem inflammatory disoder, viral infections, HLH
Likely inborn error of metabolism v2.112 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type IId 607091 to Congenital disorder of glycosylation, type IId, OMIM:607091
Undiagnosed metabolic disorders v1.453 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type IId 607091; Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type IId, OMIM:607091
Congenital disorders of glycosylation v2.67 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Congenital disorder of glycosylation, type IId 607091; Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type IId, OMIM:607091
Intellectual disability v3.1023 B4GALT1 Arina Puzriakova Publications for gene: B4GALT1 were set to 26503795; 24896178; 11901181; 21920538; 30653653
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Classified gene: B4GALT1 as Amber List (moderate evidence)
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now there are 2 families (4 total) exhibiting severe cognitive impairment, albeit this resolved in the singleton by age 11 (remaining patients were age 2.5, 11 and 11 years at the time of reporting)
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Gene: b4galt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1021 B4GALT1 Arina Puzriakova reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 21920538, 30653653, 32157688; Phenotypes: Congenital disorder of glycosylation, type IId, OMIM:607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.123 TDP2 Ivone Leong Phenotypes for gene: TDP2 were changed from Spinocerebellar ataxia, autosomal recessive 23, 616949 to Spinocerebellar ataxia, autosomal recessive 23, OMIM:616949
Structural eye disease v1.66 TBC1D23 Ivone Leong gene: TBC1D23 was added
gene: TBC1D23 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: TBC1D23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D23 were set to 28823707; 28823706; 32360255
Phenotypes for gene: TBC1D23 were set to coloboma, MONDO:0001476; strabismus, MONDO:0003432
Review for gene: TBC1D23 was set to RED
Added comment: PMID:28823707. 2 of 3 unrelated families (4 of 7 affected individuals) had ataxia. 1 family (3 affected individuals) had coloboma and strabismus. 1 family (1 individual) had hyperopia and strabismus.

PMID:28823706. 2 of 4 unrelated families (4 of 6 affected individuals) had ataxia. 2 of 6 individuals with eye phenotype (strabismus or esotropia of the left eye). Zebrafish morpholino knockout model showed reduced eye size.

PMID: 32360255. 1 case with ataxia. No eye phenotype reported.

Despite there being a zebrafish model with an eye phenotype, there is only 1 family out of 8 who had coloboma, therefore this gene is given a Red rating until more evidence is available.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.122 TBC1D23 Ivone Leong Phenotypes for gene: TBC1D23 were changed from Pontocerebellar hypoplasia, type 11, MIM# 617695 to Pontocerebellar hypoplasia, type 11, OMIM:617695
Ataxia and cerebellar anomalies - childhood onset v2.121 TBC1D23 Ivone Leong Classified gene: TBC1D23 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.121 TBC1D23 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.121 TBC1D23 Ivone Leong Gene: tbc1d23 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.120 TBC1D23 Ivone Leong Tag Q2_21_rating tag was added to gene: TBC1D23.
Ataxia and cerebellar anomalies - childhood onset v2.120 TBC1D23 Ivone Leong Added comment: Comment on publications: PMID:28823707. 2 of 3 unrelated families (4 of 7 affected individuals) had ataxia. 1 family (3 affected individuals) had coloboma and strabismus. 1 family (1 individual) had hyperopia and strabismus.

PMID:28823706. 2 of 4 unrelated families (4 of 6 affected individuals) had ataxia. 2 of 6 individuals with eye phenotype (strabismus or esotropia of the left eye).

PMID: 32360255. 1 case with ataxia. No eye phenotype reported.
Ataxia and cerebellar anomalies - childhood onset v2.120 TBC1D23 Ivone Leong Publications for gene: TBC1D23 were set to 28823707; 28823706
Intellectual disability v3.1021 B4GALT1 Arina Puzriakova Publications for gene: B4GALT1 were set to 26503795; 24896178; 11901181; 21920538
Intellectual disability v3.1020 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Congenital disorder of glycosylation, type IId 607091 to Congenital disorder of glycosylation, type IId, OMIM:607091
Intellectual disability v3.1019 AGO1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: AGO1.
Intellectual disability v3.1019 AGO1 Arina Puzriakova commented on gene: AGO1
Intellectual disability v3.1019 AGO1 Arina Puzriakova Publications for gene: AGO1 were set to 26350204; 30213762; 22495306; 23020937; 25363768; 25356899; 27620904; 29346770
Ataxia and cerebellar anomalies - childhood onset v2.119 SQSTM1 Ivone Leong Classified gene: SQSTM1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.119 SQSTM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.119 SQSTM1 Ivone Leong Gene: sqstm1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.118 SQSTM1 Ivone Leong Tag Q2_21_rating tag was added to gene: SQSTM1.
Ataxia and cerebellar anomalies - childhood onset v2.118 SQSTM1 Ivone Leong Publications for gene: SQSTM1 were set to 27545679
Ataxia and cerebellar anomalies - childhood onset v2.117 SQSTM1 Ivone Leong Phenotypes for gene: SQSTM1 were changed from Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145 to Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, OMIM:617145
Ataxia and cerebellar anomalies - childhood onset v2.116 SPR Ivone Leong Classified gene: SPR as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.116 SPR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.116 SPR Ivone Leong Gene: spr has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.115 SPR Ivone Leong Tag Q2_21_rating tag was added to gene: SPR.
Ataxia and cerebellar anomalies - childhood onset v2.115 SPR Ivone Leong Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Ataxia and cerebellar anomalies - childhood onset v2.114 SPG7 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Spastic paraplegia 7 (#607259) complex forms of the disease. Actually associated with a range of phenotypes including adult-onset ataxia
Ataxia and cerebellar anomalies - childhood onset v2.114 SPG7 Ivone Leong Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7 (#607259) complex forms of the disease. Actually associated with a range of phenotypes including adult-onset ataxia to Spastic paraplegia 7, autosomal recessive, OMIM:607259
Ataxia and cerebellar anomalies - childhood onset v2.113 SPG7 Ivone Leong Publications for gene: SPG7 were set to PMID: 25681447
Ataxia and cerebellar anomalies - childhood onset v2.112 SNAP25 Ivone Leong Classified gene: SNAP25 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.112 SNAP25 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.112 SNAP25 Ivone Leong Gene: snap25 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.111 SNAP25 Ivone Leong Tag Q2_21_rating tag was added to gene: SNAP25.
Ataxia and cerebellar anomalies - childhood onset v2.111 SNAP25 Ivone Leong Phenotypes for gene: SNAP25 were changed from Myasthenic syndrome, congenital, 18, 616330; cerebellar ataxia and seizures to ?Myasthenic syndrome, congenital, 18, OMIM:616330; cerebellar ataxia, MONDO:0000437; seizures, HP:0001250
Skeletal ciliopathies v1.10 PDIA6 Zornitza Stark gene: PDIA6 was added
gene: PDIA6 was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDIA6 were set to 33495992
Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes
Review for gene: PDIA6 was set to AMBER
Added comment: 1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans.

Rated Amber in view of the high impact variant combined with functional data including a mouse model.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.110 EXOSC1 Zornitza Stark gene: EXOSC1 was added
gene: EXOSC1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: EXOSC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC1 were set to 33463720
Phenotypes for gene: EXOSC1 were set to Pontocerebellar hypoplasia
Review for gene: EXOSC1 was set to RED
Added comment: An 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism, hypotonia, pontocerebellar hypoplasia and delayed myelination. Similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Exome sequencing revealed a homozygous missense variant (c.104C >T, p.Ser35Leu) in EXOSC1. In silico mutagenesis revealed loss of a polar contact with neighbouring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. Of note, bi‐allelic variants in other exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively.
Sources: Literature
Clefting v2.24 MED12 Zornitza Stark reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33244166; Phenotypes: Hardikar syndrome, OMIM #612726; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1018 UBE4A Zornitza Stark gene: UBE4A was added
gene: UBE4A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability
Review for gene: UBE4A was set to GREEN
gene: UBE4A was marked as current diagnostic
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Intellectual disability v3.1018 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism
Review for gene: MAPKAPK5 was set to GREEN
gene: MAPKAPK5 was marked as current diagnostic
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Borderline Amber/Green but high impact variants and a distinctive phenotype with some functional data.
Sources: Literature
Intellectual disability v3.1018 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID 33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Distal myopathies v1.29 GIPC1 Zornitza Stark edited their review of gene: GIPC1: Added comment: PMID 33374016: a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases). The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident.; Changed publications: 32413282, 33374016
Retinal disorders v2.177 CTNNA1 Zornitza Stark edited their review of gene: CTNNA1: Added comment: In addition, three independent families reported with familial exudative vitreoretinopathy (FEVR) in PMID33497368.; Changed publications: 26691986, 33497368; Changed phenotypes: Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970, Familial exudative vitreoretinopathy
Arthrogryposis v3.91 ERBB3 Zornitza Stark reviewed gene: ERBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33720042; Phenotypes: Hirschsprung disease, arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.38 CLDN11 Zornitza Stark gene: CLDN11 was added
gene: CLDN11 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy
Review for gene: CLDN11 was set to GREEN
gene: CLDN11 was marked as current diagnostic
Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 SYK Zornitza Stark reviewed gene: SYK: Rating: GREEN; Mode of pathogenicity: None; Publications: 33782605; Phenotypes: Immune dysregulation and systemic inflammation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1018 NCDN Zornitza Stark gene: NCDN was added
gene: NCDN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to GREEN
Added comment: Four families reported, all with de novo missense variants except for 1 consanguineous family where 3 affecteds were homozygous and carrier parents unaffected. ID ranged from mild to severe, several had seizures. Green for mono-allelic disease, Red for bi-allelic.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.90 TSPOAP1 Zornitza Stark gene: TSPOAP1 was added
gene: TSPOAP1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Review for gene: TSPOAP1 was set to GREEN
Added comment: 7 affecteds from 3 families (1 consanguineous)
2x null, 1x missense

Affecteds with the null variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy while those with the missense p.(Gly1808Ser) presented with isolated adult-onset focal dystonia (mild cognitive impairment noted). Mouse model.
Sources: Literature
Mitochondrial disorders v2.24 NDUFA12 Zornitza Stark reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33715266; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23 MIM#618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.91 FBN2 Zornitza Stark reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33571691; Phenotypes: Contractural arachnodactyly, congenital MIM#121050; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mitochondrial disorders v2.24 NDUFB7 Zornitza Stark reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: None; Publications: 33502047, 27626371; Phenotypes: Congenital lactic acidosis, hypertrophic cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1018 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Skeletal dysplasia v2.87 NMNAT1 Zornitza Stark gene: NMNAT1 was added
gene: NMNAT1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: NMNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT1 were set to 32533184
Phenotypes for gene: NMNAT1 were set to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260
Review for gene: NMNAT1 was set to GREEN
gene: NMNAT1 was marked as current diagnostic
Added comment: The association with LCA is well established.

New report of a syndromic LCA disorder and note also unusual variant type. Three families, but two are distantly related (shared haplotype). The affected children in those two families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant.
Sources: Literature
Primary lymphoedema v2.8 RORC Zornitza Stark gene: RORC was added
gene: RORC was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: RORC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RORC were set to 32960152
Phenotypes for gene: RORC were set to Lymphoedema
Review for gene: RORC was set to AMBER
Added comment: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency. Moderate/limited evidence for gene-disease association.
Sources: Literature
Primary lymphoedema v2.8 ARAP3 Zornitza Stark gene: ARAP3 was added
gene: ARAP3 was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARAP3 were set to 32908855
Phenotypes for gene: ARAP3 were set to Lymphoedema
Review for gene: ARAP3 was set to AMBER
Added comment: Three unrelated families reported with rare missense variants in this gene as part of a lymphoedema cohort. However, incomplete information regarding segregation and no supporting functional data.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.30 MCM10 Zornitza Stark gene: MCM10 was added
gene: MCM10 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM10 were set to 33712616
Phenotypes for gene: MCM10 were set to Restrictive cardiomyopathy
Review for gene: MCM10 was set to RED
Added comment: PMID 33712616: three affected sibs with restrictive cardiomyopathy and hypoplasia of the spleen and thymus. Functional data suggested that MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion.
Sources: Literature
Malformations of cortical development v2.44 ATP1A3 Zornitza Stark gene: ATP1A3 was added
gene: ATP1A3 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: ATP1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A3 were set to 33762331
Phenotypes for gene: ATP1A3 were set to Polymicrogyria; epilepsy; developmental delay
Review for gene: ATP1A3 was set to GREEN
gene: ATP1A3 was marked as current diagnostic
Added comment: Eight individuals with de novo variants reported and a phenotype distinct from those previously reported in association with this gene.
Sources: Literature
Primary ovarian insufficiency v1.22 HSF2BP Zornitza Stark gene: HSF2BP was added
gene: HSF2BP was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237
Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245
Review for gene: HSF2BP was set to RED
Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters.
Sources: Literature
Malformations of cortical development v2.44 SLC35A2 Zornitza Stark changed review comment from: >20 individuals reported. However note variants were identified on deep sequencing of affected tissue, and are somatic.
Sources: Literature; to: >20 individuals reported. However note variants were identified on deep sequencing of affected tissue, and are somatic. Rated as Amber as uncertain whether panel only caters to germline sequencing.
Sources: Literature
Malformations of cortical development v2.44 SLC35A2 Zornitza Stark gene: SLC35A2 was added
gene: SLC35A2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: SLC35A2 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: SLC35A2 were set to 33407896
Phenotypes for gene: SLC35A2 were set to Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)
Review for gene: SLC35A2 was set to AMBER
Added comment: >20 individuals reported. However note variants were identified on deep sequencing of affected tissue, and are somatic.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 IL37 Zornitza Stark gene: IL37 was added
gene: IL37 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.114 ABCC9 Ivone Leong Phenotypes for gene: ABCC9 were changed from Hypertrichotic osteochondrodysplasia, MIM# 239850; Cantu syndrome to Hypertrichotic osteochondrodysplasia, OMIM:239850; Cantu syndrome
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.113 ASXL2 Ivone Leong Publications for gene: ASXL2 were set to 27693232
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.112 PDGFRB Ivone Leong Classified gene: PDGFRB as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.112 PDGFRB Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.112 PDGFRB Ivone Leong Gene: pdgfrb has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.111 PDGFRB Ivone Leong Phenotypes for gene: PDGFRB were changed from Kosaki overgrowth syndrome, MIM# 616592 to Kosaki overgrowth syndrome, OMIM:616592
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.110 PIK3CA Ivone Leong Classified gene: PIK3CA as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.110 PIK3CA Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on expert reviews. This gene is associated with a relevant phenotype in OMIM and Gen2Phenotype.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.110 PIK3CA Ivone Leong Gene: pik3ca has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.109 PIK3CA Ivone Leong Phenotypes for gene: PIK3CA were changed from Human overgrowth syndrome type; Overgrowth with Intellectual disability to Human overgrowth syndrome type; Overgrowth with Intellectual disability; CLOVES: CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.108 PIK3CA Ivone Leong Mode of inheritance for gene: PIK3CA was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.107 RNF125 Ivone Leong Classified gene: RNF125 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.107 RNF125 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.107 RNF125 Ivone Leong Gene: rnf125 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.106 RNF125 Ivone Leong Phenotypes for gene: RNF125 were changed from Tenorio syndrome, MIM# 616260 to Tenorio syndrome, OMIM:616260
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.105 SETD2 Ivone Leong Classified gene: SETD2 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.105 SETD2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.105 SETD2 Ivone Leong Gene: setd2 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.104 SETD2 Ivone Leong Phenotypes for gene: SETD2 were changed from Luscan-Lumish syndrome, 616831 to Luscan-Lumish syndrome, OMIM:616831
Glaucoma (developmental) v1.34 FOXD3 Ivone Leong Classified gene: FOXD3 as Amber List (moderate evidence)
Glaucoma (developmental) v1.34 FOXD3 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Amber. Based on the expert reviews, this gene has been demoted from Green to Amber until new evidence is available.
Glaucoma (developmental) v1.34 FOXD3 Ivone Leong Gene: foxd3 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.65 LMX1B Ivone Leong Classified gene: LMX1B as Amber List (moderate evidence)
Structural eye disease v1.65 LMX1B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is Green on Glaucoma (developmental) (Version 1.33).

"Glaucoma is a key feature of this condition. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Structural eye disease v1.65 LMX1B Ivone Leong Gene: lmx1b has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.64 LMX1B Ivone Leong Phenotypes for gene: LMX1B were changed from Nail-patella syndrome, 161200 to Nail-patella syndrome, OMIM:161200
Structural eye disease v1.63 LMX1B Ivone Leong Tag Q2_21_rating tag was added to gene: LMX1B.
Glaucoma (developmental) v1.33 LMX1B Ivone Leong Classified gene: LMX1B as Green List (high evidence)
Glaucoma (developmental) v1.33 LMX1B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.33 LMX1B Ivone Leong Gene: lmx1b has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.32 LMX1B Ivone Leong Phenotypes for gene: LMX1B were changed from Nail-patella syndrome, MIM# 161200 to Nail-patella syndrome, OMIM:161200
Glaucoma (developmental) v1.31 PAX6 Ivone Leong Classified gene: PAX6 as Green List (high evidence)
Glaucoma (developmental) v1.31 PAX6 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.31 PAX6 Ivone Leong Gene: pax6 has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.30 SH3PXD2B Ivone Leong Classified gene: SH3PXD2B as Green List (high evidence)
Glaucoma (developmental) v1.30 SH3PXD2B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is also Green on Structural eye disease (Version 1.63). Macrocornea could present with or without glaucoma. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.30 SH3PXD2B Ivone Leong Gene: sh3pxd2b has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.29 SH3PXD2B Ivone Leong Publications for gene: SH3PXD2B were set to
Glaucoma (developmental) v1.28 SH3PXD2B Ivone Leong Phenotypes for gene: SH3PXD2B were changed from Frank-ter Haar syndrome, MIM# 249420 to Frank-ter Haar syndrome, OMIM:249420
Structural eye disease v1.63 CREBBP Ivone Leong Classified gene: CREBBP as Amber List (moderate evidence)
Structural eye disease v1.63 CREBBP Ivone Leong Gene: crebbp has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.62 CREBBP Ivone Leong gene: CREBBP was added
gene: CREBBP was added to Structural eye disease. Sources: Literature
Q2_21_rating tags were added to gene: CREBBP.
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CREBBP were set to 25599811
Phenotypes for gene: CREBBP were set to Rubinstein-Taybi syndrome 1, OMIM:180849
Review for gene: CREBBP was set to GREEN
Added comment: This gene is Green on Glaucoma (developmental) (Version 1.27).

"Glaucoma is a feature of this syndrome. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be given a Green rating at the next review.
Sources: Literature
Glaucoma (developmental) v1.27 CREBBP Ivone Leong Classified gene: CREBBP as Green List (high evidence)
Glaucoma (developmental) v1.27 CREBBP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.27 CREBBP Ivone Leong Gene: crebbp has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.26 CREBBP Ivone Leong Publications for gene: CREBBP were set to
Glaucoma (developmental) v1.25 CREBBP Ivone Leong Phenotypes for gene: CREBBP were changed from Rubinstein Taybi syndrome to Rubinstein-Taybi syndrome 1, OMIM:180849
Structural eye disease v1.61 TEK Ivone Leong Classified gene: TEK as Amber List (moderate evidence)
Structural eye disease v1.61 TEK Ivone Leong Gene: tek has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.60 TEK Ivone Leong gene: TEK was added
gene: TEK was added to Structural eye disease. Sources: Literature
Q2_21_rating tags were added to gene: TEK.
Mode of inheritance for gene: TEK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TEK were set to 27270174
Phenotypes for gene: TEK were set to Glaucoma 3, primary congenital, E, OMIM:617272
Review for gene: TEK was set to GREEN
Added comment: This gene is also Green on the Glaucoma (developmental) (Version 1.24).

"Ten families and a supportive mouse model. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Sources: Literature
Structural eye disease v1.59 IFIH1 Ivone Leong Classified gene: IFIH1 as Amber List (moderate evidence)
Structural eye disease v1.59 IFIH1 Ivone Leong Gene: ifih1 has been classified as Amber List (Moderate Evidence).
Glaucoma (developmental) v1.24 TEK Ivone Leong Classified gene: TEK as Green List (high evidence)
Glaucoma (developmental) v1.24 TEK Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.24 TEK Ivone Leong Gene: tek has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.23 TEK Ivone Leong Phenotypes for gene: TEK were changed from Glaucoma 3, primary congenital, E, MIM# 617272 to Glaucoma 3, primary congenital, E, OMIM:617272
Structural eye disease v1.58 IFIH1 Ivone Leong gene: IFIH1 was added
gene: IFIH1 was added to Structural eye disease. Sources: Literature
Q2_21_rating tags were added to gene: IFIH1.
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IFIH1 were set to 29703882; 31898846
Phenotypes for gene: IFIH1 were set to Singleton-Merten syndrome 1, OMIM:182250
Review for gene: IFIH1 was set to GREEN
Added comment: This gene is also Green on the Glaucoma (developmental) (Version 1.22) panel.

"Glaucoma is a feature of this condition. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

PMID: 29703882. "4-year-old boy with a diagnosis of AGS, global developmental delay, glucose-6-phosphate dehydrogenase (G6PD) deficiency, patent ductus arteriosus (PDA), congenital glaucoma, and aniridia. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents were carriers of congenital glaucoma genes." PMID: 31898846. Glaucoma found as part of the phenotype.

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-disease association. This gene should be given a Green rating at the next review.
Sources: Literature
Glaucoma (developmental) v1.22 IFIH1 Ivone Leong Classified gene: IFIH1 as Green List (high evidence)
Glaucoma (developmental) v1.22 IFIH1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.22 IFIH1 Ivone Leong Gene: ifih1 has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.21 IFIH1 Ivone Leong Added comment: Comment on publications: PMID: 29703882. "4-year-old boy with a diagnosis of AGS, global developmental delay, glucose-6-phosphate dehydrogenase (G6PD) deficiency, patent ductus arteriosus (PDA), congenital glaucoma, and aniridia. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents were carriers of congenital glaucoma genes."

PMID: 31898846. Glaucoma found as part of the phenotype.
Glaucoma (developmental) v1.21 IFIH1 Ivone Leong Publications for gene: IFIH1 were set to
Glaucoma (developmental) v1.20 IFIH1 Ivone Leong Phenotypes for gene: IFIH1 were changed from Singleton-Merten syndrome 1, MIM# 182250 to Singleton-Merten syndrome 1, OMIM:182250
Structural eye disease v1.57 OCRL Ivone Leong commented on gene: OCRL: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Glaucoma is present in ~50% of cases, GeneReviews. Therefore this gene should be promoted to Green status at the next review.
Structural eye disease v1.57 OCRL Ivone Leong Tag Q2_21_rating tag was added to gene: OCRL.
Structural eye disease v1.57 OCRL Ivone Leong Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000 to Lowe syndrome, OMIM:309000
Glaucoma (developmental) v1.19 OCRL Ivone Leong Classified gene: OCRL as Green List (high evidence)
Glaucoma (developmental) v1.19 OCRL Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association, therefore this gene has been promoted to Green.
Glaucoma (developmental) v1.19 OCRL Ivone Leong Gene: ocrl has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.18 OCRL Ivone Leong Phenotypes for gene: OCRL were changed from Lowe syndrome, MIM# 309000 to Lowe syndrome, OMIM:309000
Glaucoma (developmental) v1.17 OCRL Ivone Leong Publications for gene: OCRL were set to
Glaucoma (developmental) v1.16 SBF2 Ivone Leong Classified gene: SBF2 as Green List (high evidence)
Glaucoma (developmental) v1.16 SBF2 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is also Green on the Structural eye disease panel (Version 1.56).
Glaucoma (developmental) v1.16 SBF2 Ivone Leong Gene: sbf2 has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.14 SBF2 Ivone Leong Phenotypes for gene: SBF2 were changed from Charcot-Marie-Tooth disease, type 4B2 604563; CMT with early onset glaucoma to Charcot-Marie-Tooth disease, type 4B2, OMIM:604563; CMT with early onset glaucoma
Glaucoma (developmental) v1.13 SBF2 Ivone Leong Publications for gene: SBF2 were set to
Familial non syndromic congenital heart disease v1.60 ADAMTS19 Ivone Leong Classified gene: ADAMTS19 as Green List (high evidence)
Familial non syndromic congenital heart disease v1.60 ADAMTS19 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene is therefore given a Green rating.
Familial non syndromic congenital heart disease v1.60 ADAMTS19 Ivone Leong Gene: adamts19 has been classified as Green List (High Evidence).
Familial non syndromic congenital heart disease v1.59 ADAMTS19 Ivone Leong Phenotypes for gene: ADAMTS19 were changed from Non-syndromic heart valve disease to Non-syndromic heart valve disease; heart valve disease, MONDO:0002869
Familial non syndromic congenital heart disease v1.58 ADAMTS19 Ivone Leong Publications for gene: ADAMTS19 were set to 31844321
Thoracic aortic aneurysm or dissection (GMS) v1.7 THSD4 Ivone Leong Classified gene: THSD4 as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.7 THSD4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is no phenotypes associated with this gene in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Thoracic aortic aneurysm or dissection (GMS) v1.7 THSD4 Ivone Leong Gene: thsd4 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.6 THSD4 Ivone Leong Tag Q2_21_rating tag was added to gene: THSD4.
Thoracic aortic aneurysm or dissection (GMS) v1.6 THSD4 Ivone Leong Phenotypes for gene: THSD4 were changed from Thoracic aortic aneurysm and dissection (TAAD) to familial thoracic aortic aneurysm and aortic dissection, MONDO:0019625
Thoracic aortic aneurysm or dissection (GMS) v1.5 HEY2 Ivone Leong Classified gene: HEY2 as Red List (low evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.5 HEY2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Thoracic aortic aneurysm or dissection (GMS) v1.5 HEY2 Ivone Leong Gene: hey2 has been classified as Red List (Low Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.4 HEY2 Ivone Leong Phenotypes for gene: HEY2 were changed from congenital heart defects and thoracic aortic aneurysms to congenital heart defects, multiple type, MONDO:0000119; thoracic aortic aneurysm, MONDO:0005396
Pulmonary arterial hypertension v2.13 KDR Ivone Leong edited their review of gene: KDR: Added comment: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. This gene is also identified as a novel PAH disease gene in PMID:29650961, which was found in 4 cases and 0 in controls. Clingen has curated this gene-disease association and given it a Strong rating. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Pulmonary arterial hypertension v2.13 KDR Ivone Leong Tag watchlist was removed from gene: KDR.
Tag Q2_21_rating tag was added to gene: KDR.
Pulmonary arterial hypertension v2.13 KDR Ivone Leong Publications for gene: KDR were set to 31980491; 32880713; 33320693
Pulmonary arterial hypertension v2.12 KDR Ivone Leong Phenotypes for gene: KDR were changed from Pulmonary hypertension to Heritable pulmonary arterial hypertension, MONDO:0017148
Pulmonary arterial hypertension v2.11 KDR Ivone Leong Publications for gene: KDR were set to 31980491; 32880713
Pulmonary arterial hypertension v2.10 AQP1 Ivone Leong Tag watchlist tag was added to gene: AQP1.
Pulmonary arterial hypertension v2.10 AQP1 Ivone Leong reviewed gene: AQP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1018 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31978615, 31938306, 25338135, 20011524; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.30 RHBDF1 Zornitza Stark gene: RHBDF1 was added
gene: RHBDF1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: RHBDF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHBDF1 were set to 32870709
Phenotypes for gene: RHBDF1 were set to Dilated cardiomyopathy
Review for gene: RHBDF1 was set to AMBER
Added comment: Three families reported with homozygous variants in this gene and onset of DCM in infancy/childhood. Two of the families had the same truncating variant, indicative of founder effect, and one family had a homozygous missense variant.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.30 MYLK3 Zornitza Stark gene: MYLK3 was added
gene: MYLK3 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy
Review for gene: MYLK3 was set to AMBER
Added comment: Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Pulmonary arterial hypertension v2.10 AQP1 Ivone Leong Phenotypes for gene: AQP1 were changed from Heritable pulmonary arterial hypertension; HPAH to Heritable pulmonary arterial hypertension, HPAH, MONDO:0017148
Dilated and arrhythmogenic cardiomyopathy v1.19 FLII Ivone Leong Classified gene: FLII as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.19 FLII Ivone Leong Gene: flii has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.18 FLII Ivone Leong gene: FLII was added
gene: FLII was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Q2_21_rating tags were added to gene: FLII.
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 32870709
Phenotypes for gene: FLII were set to Dilated cardiomyopathy, MONDO:0005021
Review for gene: FLII was set to GREEN
Added comment: This gene is also on Cardiomyopathies - including childhood onset (Version 1.30).

"Two unrelated families reported with homozygous missense variants in PMID 32870709. Geng (2021): Shown to affect sarcomere size in Drosophila model. FliI knockdown resulted in disorganised myofibrils and increase filamentous actin. Campbell (2002): Hom mice - lethal, het - normal. K/O mouse model of related genes have cytoskeletal actin alterations. No survivors to observed cardiac phenotypes. We are aware of a third family ascertained through our laboratory. Sources: Literature
Zornitza Stark (Australian Genomics), 15 Apr 2021"

This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.30 FLII Ivone Leong Classified gene: FLII as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.30 FLII Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.30 FLII Ivone Leong Gene: flii has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.29 FLII Ivone Leong Tag Q2_21_rating tag was added to gene: FLII.
Paediatric or syndromic cardiomyopathy v1.29 FLII Ivone Leong Phenotypes for gene: FLII were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Paediatric disorders - additional genes v1.86 PLD1 Ivone Leong commented on gene: PLD1: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric disorders - additional genes v1.86 PLD1 Ivone Leong Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental to Cardiac valvular defect, developmental, OMIM:212093
Paediatric disorders - additional genes v1.85 PLD1 Ivone Leong Added comment: Comment on publications: PMID 33645542: 31 individuals from 20 families reported, presenting predominantly with congenital cardiac valve defects and some with neonatal cardiomyopathy. p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%). Sources: Literature
Zornitza Stark (Australian Genomics), 15 Apr 2021
Paediatric disorders - additional genes v1.85 PLD1 Ivone Leong Publications for gene: PLD1 were set to 27799408
Paediatric disorders - additional genes v1.84 PLD1 Ivone Leong Tag Q2_21_rating tag was added to gene: PLD1.
Paediatric or syndromic cardiomyopathy v1.28 PLD1 Ivone Leong Classified gene: PLD1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.28 PLD1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.28 PLD1 Ivone Leong Gene: pld1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.27 PLD1 Ivone Leong Tag Q2_21_rating tag was added to gene: PLD1.
Paediatric or syndromic cardiomyopathy v1.27 PLD1 Ivone Leong Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy to Cardiac valvular defect, developmental, OMIM:212093; neonatal cardiomyopathy
Dilated and arrhythmogenic cardiomyopathy v1.17 RPL3L Ivone Leong Classified gene: RPL3L as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.17 RPL3L Ivone Leong Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.16 RPL3L Ivone Leong gene: RPL3L was added
gene: RPL3L was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Q2_21_rating tags were added to gene: RPL3L.
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021
Review for gene: RPL3L was set to GREEN
Added comment: This gene is also present on the Cardiomyopathies - including childhood onset (Version 1.26) panel.

Review by Zornitza Stark:
"PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype."

This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.26 RPL3L Ivone Leong Classified gene: RPL3L as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.26 RPL3L Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.26 RPL3L Ivone Leong Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.25 RPL3L Ivone Leong Tag Q2_21_rating tag was added to gene: RPL3L.
Paediatric or syndromic cardiomyopathy v1.25 RPL3L Ivone Leong Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy to Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021
Paediatric or syndromic cardiomyopathy v1.24 MIB1 Ivone Leong commented on gene: MIB1: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene has been tagged and will be submitted to the GMS specialist group for review.
Paediatric or syndromic cardiomyopathy v1.24 MIB1 Ivone Leong Phenotypes for gene: MIB1 were changed from Left ventricular noncompaction 7 to Left ventricular noncompaction 7, OMIM:615092
Paediatric or syndromic cardiomyopathy v1.23 MIB1 Ivone Leong Publications for gene: MIB1 were set to
Paediatric or syndromic cardiomyopathy v1.22 MIB1 Ivone Leong Tag Q2_21_rating tag was added to gene: MIB1.
Tag Q2_21_NHS_review tag was added to gene: MIB1.
Paediatric or syndromic cardiomyopathy v1.22 COX6B1 Ivone Leong commented on gene: COX6B1: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. It is recommended that this gene should be demoted to Amber/Red at the next review.
Paediatric or syndromic cardiomyopathy v1.22 COX6B1 Ivone Leong Tag Q2_21_rating tag was added to gene: COX6B1.
Paediatric or syndromic cardiomyopathy v1.22 COX14 Ivone Leong Phenotypes for gene: COX14 were changed from ?Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, OMIM:220110
Paediatric or syndromic cardiomyopathy v1.21 COX14 Ivone Leong Tag Q2_21_rating tag was added to gene: COX14.
Paediatric or syndromic cardiomyopathy v1.21 COX14 Ivone Leong commented on gene: COX14: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. It is recommended that this gene should be demoted to Amber/Red at the next review.
Paediatric or syndromic cardiomyopathy v1.21 COX14 Ivone Leong Publications for gene: COX14 were set to
Ataxia and cerebellar anomalies - childhood onset v2.110 MSTO1 Sarah Leigh Tag Q2_21_rating tag was added to gene: MSTO1.
Ataxia and cerebellar anomalies - childhood onset v2.110 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least eight variants reported in five unrelated cases of recessive Myopathy, mitochondrial, and ataxia and one variant reported in dominant Myopathy, mitochondrial, and ataxia in one family, together with supportive functional studies (PMID 28554942).; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.110 MSTO1 Sarah Leigh Classified gene: MSTO1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.110 MSTO1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.110 MSTO1 Sarah Leigh Gene: msto1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.24 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Hereditary ataxia, adult onset v2.40 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Mitochondrial myopathy and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Likely inborn error of metabolism v2.111 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Possible mitochondrial disorder, nuclear genes v1.40 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Congenital muscular dystrophy v2.7 MSTO1 Sarah Leigh changed review comment from: Comment on phenotypes: Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Congenital muscular dystrophy with Brain involvment; to: Comment on phenotypes:
Congenital muscular dystrophy with Brain involvment
Congenital muscular dystrophy v2.7 MSTO1 Sarah Leigh Added comment: Comment on phenotypes: Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Congenital muscular dystrophy with Brain involvment
Congenital muscular dystrophy v2.7 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Congenital muscular dystrophy with Brain involvment; Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Ataxia and cerebellar anomalies - childhood onset v2.109 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, MIM# 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Monogenic hearing loss v2.160 LOXHD1 Arina Puzriakova Publications for gene: LOXHD1 were set to PMID:16936105; 19732867; 21465660; 22341973
Monogenic hearing loss v2.159 LOXHD1 Arina Puzriakova Phenotypes for gene: LOXHD1 were changed from Nonsyndromic Hearing Loss, Recessive; Deafness, autosomal recessive 77, 613079; hearing loss to Deafness, autosomal recessive 77, OMIM:613079
Intellectual disability v3.1018 LOXHD1 Arina Puzriakova Mode of inheritance for gene: LOXHD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Classified gene: KCNH1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases (>3) of epilepsy in patients with variants in the KCNH1 gene. Inclusion on this panel would be of particular benefit to individuals without typical gingival and/or nail anomalies and only mild developmental delays - who may not be tested under other panels (e.g. Limb disorders, ID) and thus may otherwise be missed in analysis.
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Gene: kcnh1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.322 KCNH1 Arina Puzriakova gene: KCNH1 was added
gene: KCNH1 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: KCNH1.
Mode of inheritance for gene: KCNH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH1 were set to 18203178; 20009591; 20683999; 21626675; 23994350; 25420144; 33811134
Phenotypes for gene: KCNH1 were set to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Review for gene: KCNH1 was set to GREEN
Added comment: Well-established cause of Temple-Baraitser syndrome (MIM #611816) and Zimmermann-Laband syndrome (MIM #135500) characterised by ID with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia. Overall, sufficient number of cases with epilepsy to rate Green on this panel (PMIDs: 18203178; 20009591; 20683999; 21626675; 23994350; 25420144)

- PMID: 33811134 (2021) - 7 patients with de novo KCNH1 variants presenting mild/moderate to severe DD/ID, but without any distinctive features of TBS/ZLS such as gingival hyperplasia and nail anomalies. Four patients had epilepsy starting in infancy, with generalised tonic–clonic (4/4), myoclonic (2/4), focal motor (2/4) and tonic (1/4) seizures. One patient experienced status epilepticus. Epilepsy was pharmacoresponsive in all individuals. This study provides evidence of KCNH-related encephalopathy even without the presence of other extra-neurological symptoms that are typically associated with pathogenic variants in this gene.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v1.15 NRAP Zornitza Stark reviewed gene: NRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33534821, 30384889, 28611399, 32870709; Phenotypes: Dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 MPEG1 Zornitza Stark gene: MPEG1 was added
gene: MPEG1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754
Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223
Review for gene: MPEG1 was set to GREEN
gene: MPEG1 was marked as current diagnostic
Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus.

Four individuals reported, functional data, including animal model.
Sources: Literature
Ichthyosis and erythrokeratoderma v1.60 ALDH1L2 Zornitza Stark gene: ALDH1L2 was added
gene: ALDH1L2 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1L2 were set to 31341639; 33168096
Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks
Review for gene: ALDH1L2 was set to RED
Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease.
Sources: Literature
Intellectual disability v3.1017 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526 to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1016 KCNH1 Arina Puzriakova Publications for gene: KCNH1 were set to 25420144; 33594261
Clefting v2.24 ESCO2 Zornitza Stark reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977150; Phenotypes: Juberg-Hayward syndrome, MIM# 216100, Roberts-SC phocomelia syndrome, MIM#268300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1015 KCNH1 Arina Puzriakova edited their review of gene: KCNH1: Changed phenotypes: Intellectual disability, Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1015 KCNH1 Arina Puzriakova reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.177 FAM57B Zornitza Stark reviewed gene: FAM57B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077892; Phenotypes: Cone–rod dystrophy, Maculopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Paediatric or syndromic cardiomyopathy v1.20 PDLIM3 Ivone Leong Publications for gene: PDLIM3 were set to 25163546
Paediatric or syndromic cardiomyopathy v1.19 PDLIM3 Ivone Leong Tag Q2_21_rating tag was added to gene: PDLIM3.
Paediatric or syndromic cardiomyopathy v1.19 PDLIM3 Ivone Leong edited their review of gene: PDLIM3: Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Variants in this gene seem to confer susceptibility to DCM but may not directly cause it (PMID: 17254821; 31424159). Therefore, this gene should be downgraded from Green to Amber/Red.; Changed publications: 17254821, 31424159
Paediatric or syndromic cardiomyopathy v1.19 FLII Zornitza Stark gene: FLII was added
gene: FLII was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 32870709
Phenotypes for gene: FLII were set to Dilated cardiomyopathy
Review for gene: FLII was set to GREEN
Added comment: Two unrelated families reported with homozygous missense variants in PMID 32870709.

Geng (2021): Shown to affect sarcomere size in Drosophila model. FliI knockdown resulted in disorganised myofibrils and increase filamentous actin.
Campbell (2002): Hom mice - lethal, het - normal. K/O mouse model of related genes have cytoskeletal actin alterations. No survivors to observed cardiac phenotypes.

We are aware of a third family ascertained through our laboratory.
Sources: Literature
Familial pulmonary fibrosis v1.13 ZCCHC8 Zornitza Stark gene: ZCCHC8 was added
gene: ZCCHC8 was added to Familial pulmonary fibrosis. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Intellectual disability v3.1015 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.19 PLD1 Zornitza Stark gene: PLD1 was added
gene: PLD1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD1 were set to 27799408; 33645542
Phenotypes for gene: PLD1 were set to Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy
Review for gene: PLD1 was set to GREEN
gene: PLD1 was marked as current diagnostic
Added comment: PMID 33645542: 31 individuals from 20 families reported, presenting predominantly with congenital cardiac valve defects and some with neonatal cardiomyopathy. p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%).
Sources: Literature
Dilated Cardiomyopathy and conduction defects v1.68 RAB3GAP2 Ivone Leong Classified gene: RAB3GAP2 as Red List (low evidence)
Dilated Cardiomyopathy and conduction defects v1.68 RAB3GAP2 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Red. There is no evidence to support this gene-disease association.
Dilated Cardiomyopathy and conduction defects v1.68 RAB3GAP2 Ivone Leong Gene: rab3gap2 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy v2.20 JPH2 Ivone Leong commented on gene: JPH2: This gene has been tagged and will be submitted for review by the GMS expert group.
Hypertrophic cardiomyopathy v2.20 JPH2 Ivone Leong Phenotypes for gene: JPH2 were changed from Cardiomyopathy, familial hypertrophic 17 (613873) to Cardiomyopathy, hypertrophic, 17, OMIM:613873
Hypertrophic cardiomyopathy v2.19 JPH2 Ivone Leong Publications for gene: JPH2 were set to 28393127; 17509612; 17476457; 30681346; 23973696; 26869393; 28393127; 30235249
Hypertrophic cardiomyopathy v2.19 JPH2 Ivone Leong Publications for gene: JPH2 were set to 28393127; 17509612; 17476457; 30681346
Hypertrophic cardiomyopathy v2.18 JPH2 Ivone Leong Tag Q2_21_expert_review tag was added to gene: JPH2.
Dilated and arrhythmogenic cardiomyopathy v1.15 TBX5 Ivone Leong Classified gene: TBX5 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.15 TBX5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Dilated and arrhythmogenic cardiomyopathy v1.15 TBX5 Ivone Leong Gene: tbx5 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.14 TBX5 Ivone Leong Tag Q2_21_rating tag was added to gene: TBX5.
Dilated and arrhythmogenic cardiomyopathy v1.14 TBX5 Ivone Leong Phenotypes for gene: TBX5 were changed from Holt-Oram syndrome, 142900; Dilated cardiomyopathy to Holt-Oram syndrome, OMIM:142900; Dilated cardiomyopathy
Ataxia and cerebellar anomalies - childhood onset v2.108 IRF2BPL Sarah Leigh Classified gene: IRF2BPL as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.108 IRF2BPL Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.108 IRF2BPL Sarah Leigh Gene: irf2bpl has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.90 IRF2BPL Sarah Leigh Classified gene: IRF2BPL as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.90 IRF2BPL Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.90 IRF2BPL Sarah Leigh Gene: irf2bpl has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.89 IRF2BPL Sarah Leigh Tag Q2_21_rating tag was added to gene: IRF2BPL.
Dystonia, chorea or related movement disorder, childhood onset v1.89 IRF2BPL Sarah Leigh reviewed gene: IRF2BPL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.89 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088 to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Dystonia, chorea or related movement disorder, childhood onset v1.88 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to 30057031; 30166628
Ataxia and cerebellar anomalies - childhood onset v2.107 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to 30057031; 30166628
Early onset or syndromic epilepsy v2.321 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to 30057031; 28135719; 25363768
Hereditary ataxia, adult onset v2.39 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to
Intellectual disability v3.1015 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures; Global developmental delay, Developmental regression, Seizures, Ataxia to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Hereditary ataxia, adult onset v2.38 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movement, loss of speech and seizures, 618088 to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Early onset or syndromic epilepsy v2.320 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures 618088 to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Arthrogryposis v3.91 STAC3 Arina Puzriakova Publications for gene: STAC3 were set to 23736855
Ataxia and cerebellar anomalies - childhood onset v2.106 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to 30057031
Ataxia and cerebellar anomalies - childhood onset v2.105 IRF2BPL Sarah Leigh reviewed gene: IRF2BPL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.43 NODAL Ivone Leong Publications for gene: NODAL were set to 19064609
Arthrogryposis v3.90 UNC50 Arina Puzriakova Classified gene: UNC50 as Red List (low evidence)
Arthrogryposis v3.90 UNC50 Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence. Only a single variant described in 2 individuals (PMIDs: 29016857; 33820833). Additional cases with different variants or strong functional support required to validate pathogenicity.
Arthrogryposis v3.90 UNC50 Arina Puzriakova Gene: unc50 has been classified as Red List (Low Evidence).
Arthrogryposis v3.89 UNC50 Arina Puzriakova Classified gene: UNC50 as Amber List (moderate evidence)
Arthrogryposis v3.89 UNC50 Arina Puzriakova Gene: unc50 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.105 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088 to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Arthrogryposis v3.88 UNC50 Arina Puzriakova gene: UNC50 was added
gene: UNC50 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC50 were set to 29016857; 33820833
Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita
Review for gene: UNC50 was set to AMBER
Added comment: UNC50 is currently not associated with any phenotype in OMIM (last edited on 02/01/2018) or Gene2Phenotype.

- PMID: 29016857 (2017) - Homozygosity mapping of disease loci combined with WES in a single male from a consanguineous family presenting with lethal AMC revealed a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4). Functional studies in C. elegans showed the variant caused loss of acetylcholine receptor expression in the muscle.

- PMID: 33820833 (2021) - Single individual reported with the same homozygous c.750_751del:p.Cys251Phefs*4 variant in UNC50 as previously described. The case was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and tetra ventricular dilation were detected prenatally.

-- Note: it isn't definitively clear whether these are different individuals. Both are singleton males born to consanguineous parents, with the same variant and similar phenotype. Also both infants died at 28 w.g. However, the 2021 paper (PMID:33820833) states their patient was selected from a cohort of cases without a molecular diagnosis and indicate the UNC50 gene had already previously been identified in relation to this phenotype, highlighting the earlier paper (PMID:29016857). There is also no mention of tetra ventricular dilation in the first case, so it is likely that these do represent distinct individuals. Additional cases needed to provide clarity.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.104 IRF2BPL Sarah Leigh Tag Q2_21_rating tag was added to gene: IRF2BPL.
Ataxia and cerebellar anomalies - childhood onset v2.104 FBXL4 Sarah Leigh edited their review of gene: FBXL4: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in five unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.104 FBXL4 Sarah Leigh Tag Q2_21_rating tag was added to gene: FBXL4.
Likely inborn error of metabolism v2.110 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: fatal encephalopathy, lactic acidosis, and severe MTDNA depletion in muscle.;Disorders of mitochondrial DNA maintenance and integrity
Likely inborn error of metabolism v2.110 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from fatal encephalopathy, lactic acidosis, and severe MTDNA depletion in muscle.; Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471 to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Ataxia and cerebellar anomalies - childhood onset v2.104 FBXL4 Sarah Leigh Classified gene: FBXL4 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.104 FBXL4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.104 FBXL4 Sarah Leigh Gene: fbxl4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.319 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: Seizures
Early onset or syndromic epilepsy v2.319 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; Seizures to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Intellectual disability v3.1014 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE
Intellectual disability v3.1014 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; FATAL ENCEPHALOPATHY, LACTIC ACIDOSIS, AND SEVERE MTDNA DEPLETION IN MUSCLE to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Mitochondrial disorders v2.23 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity;Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471;fatal encephalopathy, lactic acidosis, and severe MTDNA depletion in muscle.
Mitochondrial disorders v2.23 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; fatal encephalopathy, lactic acidosis, and severe MTDNA depletion in muscle. to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Laterality disorders and isomerism v1.42 DNAAF2 Ivone Leong commented on gene: DNAAF2: This gene is associated with a relevant disease in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review.
Laterality disorders and isomerism v1.42 DNAAF2 Ivone Leong Tag Q2_21_rating tag was added to gene: DNAAF2.
Laterality disorders and isomerism v1.42 DNAAF2 Ivone Leong Added comment: Comment on publications: PMID: 32638265 is an additional case in a non-consanguineous Han Chinese family. Proband has compound heterozygous variants in this gene and exhibited typical PCD-related clinical symptoms, including chronic otitis media, and recurrent pneumonia since birth. The proband also had chronic ethmoid and maxillary sinusitis, ring-shaped or ductal opacities throughout both lungs, bilateral lung bronchiectasis, and situs inversus totalis in the heart, liver, and colon.
Laterality disorders and isomerism v1.42 DNAAF2 Ivone Leong Publications for gene: DNAAF2 were set to 19052621; 31107948
Ataxia and cerebellar anomalies - childhood onset v2.103 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), MIM# 615471 to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
White matter disorders and cerebral calcification - childhood onset v1.38 FA2H Sarah Leigh edited their review of gene: FA2H: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least eight variants reported in seven unrelated cases.; Changed rating: GREEN
White matter disorders and cerebral calcification - childhood onset v1.38 FA2H Sarah Leigh Tag Q2_21_rating tag was added to gene: FA2H.
White matter disorders and cerebral calcification - childhood onset v1.38 FA2H Sarah Leigh Phenotypes for gene: FA2H were changed from to Spastic paraplegia 35, autosomal recessive OMIM:612319; hereditary spastic paraplegia 35 MONDO:0012866
Ataxia and cerebellar anomalies - childhood onset v2.102 FA2H Sarah Leigh Publications for gene: FA2H were set to 31135052
White matter disorders and cerebral calcification - childhood onset v1.37 FA2H Sarah Leigh Publications for gene: FA2H were set to MIM#612319
White matter disorders and cerebral calcification - childhood onset v1.36 FA2H Sarah Leigh Classified gene: FA2H as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.36 FA2H Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - childhood onset v1.36 FA2H Sarah Leigh Gene: fa2h has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.101 FA2H Sarah Leigh Tag Q2_21_rating tag was added to gene: FA2H.
Ataxia and cerebellar anomalies - childhood onset v2.101 FA2H Sarah Leigh edited their review of gene: FA2H: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least eight variants reported in seven unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.101 FA2H Sarah Leigh Classified gene: FA2H as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.101 FA2H Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.101 FA2H Sarah Leigh Gene: fa2h has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.100 FA2H Sarah Leigh Phenotypes for gene: FA2H were changed from Spastic paraplegia 35, autosomal recessive MIM#612319 to Spastic paraplegia 35, autosomal recessive OMIM:612319; hereditary spastic paraplegia 35 MONDO:0012866
Ataxia and cerebellar anomalies - childhood onset v2.99 EBF3 Sarah Leigh edited their review of gene: EBF3: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 10 variants reported in at least 11 unrelated cases.; Changed rating: GREEN
Arthrogryposis v3.87 MAGEL2 Arina Puzriakova Publications for gene: MAGEL2 were set to 26365340; 27195816; 31504653; 29359444; 24076603
Arthrogryposis v3.86 MAGEL2 Arina Puzriakova Phenotypes for gene: MAGEL2 were changed from Schaaf-Yang syndrome, 615547; ARTHROGRYPOSIS MULTIPLEX CONGENITA; Prader-Willi-Like syndrome to Schaaf-Yang syndrome, OMIM:615547; Prader-Willi-Like syndrome
Intellectual disability v3.1013 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Hypotonia, ataxia, and delayed development syndrome 617330 to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Hereditary ataxia, adult onset v2.37 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Hypotonia, ataxia and delayed development syndrome, 617330 to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
DDG2P v2.25 EBF3 Sarah Leigh Added comment: Comment on phenotypes: Intellectual Disability, Ataxia, and Facial Dysmorphism
DDG2P v2.25 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Intellectual Disability, Ataxia, and Facial Dysmorphism to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Arthrogryposis v3.85 LMOD3 Arina Puzriakova Phenotypes for gene: LMOD3 were changed from Nemaline myopathy 10 616165 to Nemaline myopathy 10, OMIM:616165
Fetal anomalies v1.641 EBF3 Sarah Leigh Added comment: Comment on phenotypes: Intellectual Disability, Ataxia, and Facial Dysmorphism
Fetal anomalies v1.641 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Intellectual Disability, Ataxia, and Facial Dysmorphism to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Arthrogryposis v3.84 LMOD3 Arina Puzriakova Publications for gene: LMOD3 were set to 25250574
Arthrogryposis v3.83 LGI4 Arina Puzriakova Phenotypes for gene: LGI4 were changed from Arthrogryposis Multiplex Congenita; Arthrogryposis multiplex congenita, neurogenic, with myelin defect, 617468; AMCNMY to Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect, OMIM:617468
Arthrogryposis v3.82 LGI4 Arina Puzriakova Publications for gene: LGI4 were set to 28318499; 15857855; 16341215
Arthrogryposis v3.81 GLDN Arina Puzriakova Phenotypes for gene: GLDN were changed from Lethal congenital contracture syndrome 11 617194 to Lethal congenital contracture syndrome 11, OMIM:617194
Arthrogryposis v3.80 GLDN Arina Puzriakova Publications for gene: GLDN were set to 27616481
Arthrogryposis v3.79 CNTNAP1 Arina Puzriakova Phenotypes for gene: CNTNAP1 were changed from Lethal congenital contracture syndrome 7 616286 to Lethal congenital contracture syndrome 7, OMIM:616286
Arthrogryposis v3.78 CNTNAP1 Arina Puzriakova Publications for gene: CNTNAP1 were set to 24319099
Ataxia and cerebellar anomalies - childhood onset v2.99 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Hypotonia, ataxia, and delayed development syndrome, MIM# 617330 to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Arthrogryposis v3.77 ADCY6 Arina Puzriakova Publications for gene: ADCY6 were set to 24319099; 26257172; 31846058
Arthrogryposis v3.76 ADCY6 Arina Puzriakova edited their review of gene: ADCY6: Added comment: - PMID: 33820833 (2021) - Further 2 sibs reported with a homozygous c.3346C>T:p.Arg1116Cys variant in the ADCY6 gene. The family was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and IUGR were detected prenatally.; Changed rating: GREEN; Changed publications: 24319099, 26257172, 31846058, 33820833; Changed phenotypes: Lethal congenital contracture syndrome 8, OMIM:616287; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.98 EBF3 Sarah Leigh Classified gene: EBF3 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.98 EBF3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.98 EBF3 Sarah Leigh Gene: ebf3 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.97 EBF3 Sarah Leigh Tag Q2_21_rating tag was added to gene: EBF3.
Ataxia and cerebellar anomalies - childhood onset v2.97 DOCK3 Sarah Leigh edited their review of gene: DOCK3: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least seven variants reported in at least five unrelated cases.; Changed rating: GREEN
Intellectual disability v3.1012 DOCK3 Sarah Leigh Phenotypes for gene: DOCK3 were changed from Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292 to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia OMIM:618292; neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia MONDO:0032661
Ataxia and cerebellar anomalies - childhood onset v2.97 DOCK3 Sarah Leigh Phenotypes for gene: DOCK3 were changed from Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, MIM#618292 to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia OMIM:618292; neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia MONDO:0032661
Ataxia and cerebellar anomalies - childhood onset v2.96 DOCK3 Sarah Leigh Tag Q2_21_rating tag was added to gene: DOCK3.
Ataxia and cerebellar anomalies - childhood onset v2.96 DOCK3 Sarah Leigh Classified gene: DOCK3 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.96 DOCK3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.96 DOCK3 Sarah Leigh Gene: dock3 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.95 DKC1 Sarah Leigh reviewed gene: DKC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.95 DKC1 Sarah Leigh Publications for gene: DKC1 were set to 9590285; 9886310; 10921354; 33734615; 10583221
Ataxia and cerebellar anomalies - childhood onset v2.94 DKC1 Sarah Leigh Publications for gene: DKC1 were set to 9590285; 9886310; 10921354
Holoprosencephaly v2.16 PLCH1 Arina Puzriakova Classified gene: PLCH1 as Amber List (moderate evidence)
Holoprosencephaly v2.16 PLCH1 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families reported in PMID:33820834 with a holoprosencephaly spectrum phenotype associated with biallelic PLCH1 variants. Rating Amber, awaiting further cases.
Holoprosencephaly v2.16 PLCH1 Arina Puzriakova Gene: plch1 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.15 PLCH1 Arina Puzriakova gene: PLCH1 was added
gene: PLCH1 was added to Holoprosencephaly. Sources: Literature
Mode of inheritance for gene: PLCH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCH1 were set to 33820834
Phenotypes for gene: PLCH1 were set to Severe developmental delay; Brain malformations; Holoprosencephaly spectrum
Review for gene: PLCH1 was set to AMBER
Added comment: PLCH1 is currently not associated with any phenotype in OMIM (last edited on 16/06/2009) or Gene2Phenotype.

- PMID: 33820834 (2021) - Two sibling pairs from two unrelated families with a holoprosencephaly spectrum phenotype and different homozygous PLCH1 variants (c.2065C>T, p.Arg689* and c.4235delA, p.Cys1079ValfsTer16, respectively). One family presented with congenital hydrocephalus, epilepsy, significant developmental delay and a monoventricle or fused thalami; while sibs from the second family had alobar holoprosencephaly and cyclopia. 3/4 individuals also displayed a cleft palate and congenital heart disease.

Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.93 DKC1 Sarah Leigh Phenotypes for gene: DKC1 were changed from X-linked dyskeratosis congenita to Dyskeratosis congenita, X-linked OMIM:305000; dyskeratosis congenita, X-linked MONDO:0010584
Ataxia and cerebellar anomalies - childhood onset v2.92 DKC1 Sarah Leigh Publications for gene: DKC1 were set to 9590285; 9886310
Hereditary spastic paraplegia, adult onset v1.17 CYP2U1 Sarah Leigh Phenotypes for gene: CYP2U1 were changed from Spastic paraplegia 56, autosomal recessive, 615030 to Spastic paraplegia 56, autosomal recessive OMIM:615030; hereditary spastic paraplegia 56 MONDO:0014015
Ataxia and cerebellar anomalies - childhood onset v2.91 CYP2U1 Sarah Leigh Added comment: Comment on phenotypes: Autosomal recessive spastic paraplegia 56 (#615030) complex form of disorder, ataxia not yet identified in affected patients.
Ataxia and cerebellar anomalies - childhood onset v2.91 CYP2U1 Sarah Leigh Phenotypes for gene: CYP2U1 were changed from Autosomal recessive spastic paraplegia 56 (#615030) complex form of disorder, ataxia not yet identified in affected patients. to Spastic paraplegia 56, autosomal recessive OMIM:615030; hereditary spastic paraplegia 56 MONDO:0014015
Ataxia and cerebellar anomalies - childhood onset v2.90 CYP2U1 Sarah Leigh Publications for gene: CYP2U1 were set to
Sporadic aniridia v2.14 PAX6 Arina Puzriakova Publications for gene: PAX6 were set to 1302030; 8111379; 7951315; 7666404; 7550230; 19876904; 9931324; 12552561; 11826019; 11553050; 17148041; 17595013; 17406642; 32467297
Adult solid tumours cancer susceptibility v2.9 PALB2 Arina Puzriakova Publications for gene: PALB2 were set to
Early onset or syndromic epilepsy v2.318 KCNQ2 Arina Puzriakova Publications for gene: KCNQ2 were set to Dedek et al (2003) Epilepsy Res 54: 21-27
Intellectual disability v3.1011 KCNQ2 Arina Puzriakova Publications for gene: KCNQ2 were set to
Hereditary neuropathy or pain disorder v1.25 VWA1 Ian Berry gene: VWA1 was added
gene: VWA1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS
Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA1 were set to PMID: 33559681
Phenotypes for gene: VWA1 were set to axonal hereditary motor neuropathy; myopathy
Penetrance for gene: VWA1 were set to unknown
Review for gene: VWA1 was set to GREEN
gene: VWA1 was marked as current diagnostic
Added comment: 17 individuals from 15 families, recurrent 10bp repeat allele causative in all patients. Detected in 100K so clearly tractable by WGS.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.317 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1); EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 7 (EIEE7); Epileptic encephalopathy, early infantile, 7; Myokymia; Seizures, benign neonatal, 1 to Developmental and epileptic encephalopathy 7, OMIM:613720; Seizures, benign neonatal, 1, OMIM:121200
Intellectual disability v3.1010 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from Seizures, benign neonatal, 1, 121200Myokymia, 121200Epileptic encephalopathy, early infantile, 7, 613720; BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1) to Developmental and epileptic encephalopathy 7, OMIM:613720
Sporadic aniridia v2.13 PAX6 Arina Puzriakova Publications for gene: PAX6 were set to 1302030; 8111379; 7951315; 7666404; 7550230; 19876904; 9931324; 12552561; 11826019; 11553050; 17148041; 17595013; 17406642
Inherited pancreatic cancer v1.18 CDKN2A Arina Puzriakova Publications for gene: CDKN2A were set to 30558719
Pigmentary skin disorders v1.10 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 2; CMM2; Melanoma susceptibility to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Adult solid tumours cancer susceptibility v2.8 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from Familial Malignant Melanoma and Tumors of the Nervous system, Familial Uveal Melanoma to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Familial melanoma v1.10 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Ataxia and cerebellar anomalies - childhood onset v2.89 CSTB Sarah Leigh Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) OMIM:254800; Unverricht-Lundborg syndrome MONDO:0009698
Dystonia, chorea or related movement disorder, childhood onset v1.87 CSTB Sarah Leigh Tag Q2_21_phenotype tag was added to gene: CSTB.
Dystonia, chorea or related movement disorder, childhood onset v1.87 CSTB Sarah Leigh Phenotypes for gene: CSTB were changed from microcephaly and severe dyskinesia; Epilepsy, progressive myoclonic 1A, 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) OMIM:254800; Unverricht-Lundborg syndrome MONDO:0009698
Ataxia and cerebellar anomalies - childhood onset v2.88 CSTB_CCCCGCCCCGCG Sarah Leigh Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) OMIM:254800; Unverricht-Lundborg syndrome MONDO:0009698
Ataxia and cerebellar anomalies - childhood onset v2.87 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Ataxia and cerebellar anomalies - childhood onset v2.87 CSTB Sarah Leigh edited their review of gene: CSTB: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in at least four unrelated cases. Some cases are compound heterozygous with STR: CSTB_CCCCGCCCCGCG; Changed rating: GREEN
Laterality disorders and isomerism v1.41 NKX2-5 Ivone Leong Added comment: Comment on phenotypes: This gene is also associated with Ventricular septal defect 3, OMIM:614432;Tetralogy of Fallot, OMIM:187500
Laterality disorders and isomerism v1.41 NKX2-5 Ivone Leong Phenotypes for gene: NKX2-5 were changed from Ventricular septal defect 3, OMIM:614432; Tetralogy of Fallot, OMIM:187500 to visceral heterotaxy, MONDO:0018677
Laterality disorders and isomerism v1.40 MYH6 Ivone Leong Added comment: Comment on phenotypes: This gene is also associated with Atrial septal defect 3, OMIM:614089
Laterality disorders and isomerism v1.40 MYH6 Ivone Leong Phenotypes for gene: MYH6 were changed from Atrial septal defect 3, OMIM:614089 to visceral heterotaxy, MONDO:0018677
Laterality disorders and isomerism v1.39 NKX2-5 Ivone Leong Phenotypes for gene: NKX2-5 were changed from to Ventricular septal defect 3, OMIM:614432; Tetralogy of Fallot, OMIM:187500
Laterality disorders and isomerism v1.38 MYH6 Ivone Leong Classified gene: MYH6 as Red List (low evidence)
Laterality disorders and isomerism v1.38 MYH6 Ivone Leong Added comment: Comment on list classification: Downgraded from Amber to Red. There is currently no evidence to support that MYH6 is associated with heterotaxy/laterality defects.
Laterality disorders and isomerism v1.38 MYH6 Ivone Leong Gene: myh6 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v1.37 MYH6 Ivone Leong Phenotypes for gene: MYH6 were changed from to Atrial septal defect 3, OMIM:614089
Laterality disorders and isomerism v1.36 MYH6 Ivone Leong Publications for gene: MYH6 were set to
Laterality disorders and isomerism v1.35 MYH6 Ivone Leong Mode of inheritance for gene: MYH6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Laterality disorders and isomerism v1.34 DNAAF2 Ivone Leong Phenotypes for gene: DNAAF2 were changed from Ciliary dyskinesia, primary, 10, 612518 to Ciliary dyskinesia, primary, 10, OMIM:612518
Laterality disorders and isomerism v1.33 DNAAF2 Ivone Leong Publications for gene: DNAAF2 were set to 19052621
Laterality disorders and isomerism v1.32 CFC1 Ivone Leong Tag Q2_21_expert_review tag was added to gene: CFC1.
Laterality disorders and isomerism v1.32 CFC1 Ivone Leong reviewed gene: CFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.32 CFC1 Ivone Leong Tag Q2_21_rating tag was added to gene: CFC1.
Laterality disorders and isomerism v1.32 CFC1 Ivone Leong Phenotypes for gene: CFC1 were changed from Heterotaxy, visceral, 2, 605376 to Heterotaxy, visceral, 2, autosomal, OMIM:605376
Laterality disorders and isomerism v1.31 CFC1 Ivone Leong Publications for gene: CFC1 were set to 11062482; 25423076
Laterality disorders and isomerism v1.30 CCDC65 Ivone Leong commented on gene: CCDC65
Ataxia and cerebellar anomalies - childhood onset v2.87 CSTB_CCCCGCCCCGCG Sarah Leigh Publications for STR: CSTB_CCCCGCCCCGCG were set to
Ataxia and cerebellar anomalies - childhood onset v2.86 CSTB Sarah Leigh Publications for gene: CSTB were set to
Ataxia and cerebellar anomalies - childhood onset v2.85 CSTB Sarah Leigh Classified gene: CSTB as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.85 CSTB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.85 CSTB Sarah Leigh Gene: cstb has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.84 CSTB Sarah Leigh Tag Q2_21_rating tag was added to gene: CSTB.
Laterality disorders and isomerism v1.30 CCDC65 Ivone Leong Phenotypes for gene: CCDC65 were changed from to Ciliary dyskinesia, primary, 27, OMIM:615504
Laterality disorders and isomerism v1.29 CCDC65 Ivone Leong Publications for gene: CCDC65 were set to
Laterality disorders and isomerism v1.28 CCDC65 Ivone Leong Mode of inheritance for gene: CCDC65 was changed from to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.84 COA7 Sarah Leigh edited their review of gene: COA7: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in at least five unrelated cases.; Changed rating: GREEN
White matter disorders and cerebral calcification - childhood onset v1.35 COA7 Sarah Leigh edited their review of gene: COA7: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in at least five unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.84 COA7 Sarah Leigh Tag Q2_21_rating tag was added to gene: COA7.
White matter disorders and cerebral calcification - childhood onset v1.35 COA7 Sarah Leigh Tag Q2_21_rating tag was added to gene: COA7.
White matter disorders and cerebral calcification - childhood onset v1.35 COA7 Sarah Leigh Classified gene: COA7 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.35 COA7 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - childhood onset v1.35 COA7 Sarah Leigh Gene: coa7 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.84 COA7 Sarah Leigh Classified gene: COA7 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.84 COA7 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.84 COA7 Sarah Leigh Gene: coa7 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.34 COA7 Sarah Leigh Publications for gene: COA7 were set to 27683825; 29718187
Ataxia and cerebellar anomalies - childhood onset v2.83 COA7 Sarah Leigh Publications for gene: COA7 were set to 29718187; 27683825
Likely inborn error of metabolism v2.109 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Mitochondrial disorder with complex IV deficiency v1.11 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3, 618387 to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
White matter disorders and cerebral calcification - childhood onset v1.33 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MIM#618387 to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Hereditary ataxia, adult onset v2.36 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from Spinocerebellar ataxia with axonal neuropathy to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Mitochondrial disorders v2.22 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Hereditary neuropathy v1.384 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3, 618387; Cerebellar atrophy, leukoencephalopathy and spinal cord atrophy in some patients. Axonal sensory and motor neuropathy to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Possible mitochondrial disorder, nuclear genes v1.39 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3, 618387 to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Ataxia and cerebellar anomalies - childhood onset v2.82 COA7 Sarah Leigh Phenotypes for gene: COA7 were changed from Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3, MIM#618387 to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 OMIM:618387; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MONDO:0020770
Intellectual disability v3.1009 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 0
Early onset or syndromic epilepsy v2.316 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder 616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Fetal anomalies v1.640 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from SEVERE INTELLECTUAL DISABILITY, EPILEPSY, AND CATARACTS to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Likely inborn error of metabolism v2.108 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, 616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Undiagnosed metabolic disorders v1.452 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Peroxisomal disorders v1.7 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder 616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Intellectual disability v3.1008 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from SEVERE INTELLECTUAL DISABILITY, EPILEPSY, AND CATARACTS to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Mitochondrial disorders v2.21 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Perrault syndrome 4, 615300; Perrault syndrome to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only); Multiple respiratory chain complex deficiencies (disorders of protein synthesis
Likely inborn error of metabolism v2.107 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Perrault syndrome; Perrault syndrome 4, 615300; Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only); Multiple respiratory chain complex deficiencies (disorders of protein synthesis
Possible mitochondrial disorder, nuclear genes v1.38 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from ?Hydrops, lactic acidosis, and sideroblastic anemia, 617021; Perrault syndrome 4, 615300 to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only); Multiple respiratory chain complex deficiencies (disorders of protein synthesis
Undiagnosed metabolic disorders v1.451 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Perrault syndrome 4, 615300; Perrault syndrome to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only); Multiple respiratory chain complex deficiencies (disorders of protein synthesis
Rare anaemia v1.21 LARS2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: LARS2.
Rare anaemia v1.21 LARS2 Arina Puzriakova reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26537577, 32442335; Phenotypes: Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare anaemia v1.21 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to
Rare anaemia v1.20 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from hydrops/sideroblastic anaemia to Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021
Ataxia and cerebellar anomalies - childhood onset v2.81 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Perrault syndrome 4, MIM# 615300; Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Leukodystrophy to Perrault syndrome 4, OMIM:615300
Leukodystrophy, adult onset v1.8 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Leukodystrophy to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Leukodystrophy
Primary ovarian insufficiency v1.22 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Perrault syndrome 4 615300 to Perrault syndrome 4, OMIM:615300
Fetal hydrops v1.28 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from ?Hydrops, lactic acidosis, and sideroblastic anemia, 617021; HLASA to Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021
Fetal hydrops v1.27 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to 26537577
Fetal hydrops v1.26 LARS2 Arina Puzriakova Classified gene: LARS2 as Green List (high evidence)
Fetal hydrops v1.26 LARS2 Arina Puzriakova Added comment: Comment on list classification: Promoted from Red to Green as there is now a sufficient number of unrelated cases (3) with evidence of fetal hydrops due to biallelic variants in this gene.
Fetal hydrops v1.26 LARS2 Arina Puzriakova Gene: lars2 has been classified as Green List (High Evidence).
Fetal hydrops v1.25 LARS2 Arina Puzriakova reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26537577, 32442335; Phenotypes: Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.639 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from PERRAULT SYNDROME to Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021
Fetal anomalies v1.638 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to
Fetal anomalies v1.637 LARS2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: LARS2.
Fetal anomalies v1.637 LARS2 Arina Puzriakova reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26537577, 32442335; Phenotypes: Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1007 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to
Intellectual disability v3.1006 LARS2 Arina Puzriakova changed review comment from: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.; to: Comment on list classification: While a few cases with neurological symptoms including developmental delay or neurologic decline have been reported (PMID: 29205794; 30737337; 32442335), this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent the main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1006 LARS2 Arina Puzriakova Classified gene: LARS2 as Amber List (moderate evidence)
Intellectual disability v3.1006 LARS2 Arina Puzriakova Added comment: Comment on list classification: While are a few cases with neurological symptoms including developmental delay have been reported, this manifestation is part of a broader phenotype where cognitive impairment is unlikely to represent a main feature. In the majority of cases, cognitive function is preserved.

Therefore, rating Amber on this panel. The phenotypes associated with LARS2 are better represented in other panels (e.g. Hearing loss) where this gene is already Green.
Intellectual disability v3.1006 LARS2 Arina Puzriakova Gene: lars2 has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.19 LARS2 Arina Puzriakova Mode of inheritance for gene: LARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.158 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from #615300: Perrault syndrome 4 to Perrault syndrome 4, OMIM:615300
Intellectual disability v3.1005 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Leukodystrophy
Intellectual disability v3.1004 LARS2 Arina Puzriakova Mode of inheritance for gene: LARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 PRIM1 Arina Puzriakova Classified gene: PRIM1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 PRIM1 Arina Puzriakova Added comment: Comment on list classification: PRIM1 was added to this panel following discussion with Helen Brittain (Genomics England Clinical Team). It was agreed that there is sufficient evidence to rate this gene Green at the next review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 PRIM1 Arina Puzriakova Gene: prim1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.412 PRIM1 Arina Puzriakova gene: PRIM1 was added
gene: PRIM1 was added to Primary immunodeficiency. Sources: Literature
Q2_21_rating tags were added to gene: PRIM1.
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to GREEN
Added comment: PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype.

- PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Severe microcephaly v2.111 PRIM1 Arina Puzriakova edited their review of gene: PRIM1: Changed rating: GREEN
Severe microcephaly v2.111 PRIM1 Arina Puzriakova Classified gene: PRIM1 as Amber List (moderate evidence)
Severe microcephaly v2.111 PRIM1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is sufficient evidence to rate this gene Green at the next review
Severe microcephaly v2.111 PRIM1 Arina Puzriakova Gene: prim1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.110 PRIM1 Arina Puzriakova Tag watchlist was removed from gene: PRIM1.
Tag Q2_21_rating tag was added to gene: PRIM1.
Laterality disorders and isomerism v1.27 NKX2-5 Ivone Leong Mode of inheritance for gene: NKX2-5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Laterality disorders and isomerism v1.26 NKX2-5 Ivone Leong Publications for gene: NKX2-5 were set to
Laterality disorders and isomerism v1.25 CFAP52 Ivone Leong Tag Q2_21_rating tag was added to gene: CFAP52.
Laterality disorders and isomerism v1.25 CFAP52 Ivone Leong Classified gene: CFAP52 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.25 CFAP52 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Laterality disorders and isomerism v1.25 CFAP52 Ivone Leong Gene: cfap52 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.24 CFAP52 Ivone Leong Phenotypes for gene: CFAP52 were changed from Heterotaxy to visceral heterotaxy, MONDO:0018677
Laterality disorders and isomerism v1.23 CFAP45 Ivone Leong Classified gene: CFAP45 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.23 CFAP45 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Laterality disorders and isomerism v1.23 CFAP45 Ivone Leong Gene: cfap45 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.22 CFAP45 Ivone Leong Phenotypes for gene: CFAP45 were changed from Situs inversus; asthenospermia to Situs inversus, MONDO:0010029; male infertility due to sperm motility disorder, MONDO:0018395
Laterality disorders and isomerism v1.21 CFAP45 Ivone Leong Tag Q2_21_rating tag was added to gene: CFAP45.
Retinal disorders v2.177 AMACR Ivone Leong Classified gene: AMACR as Amber List (moderate evidence)
Retinal disorders v2.177 AMACR Ivone Leong Added comment: Comment on list classification: New gene added by Hannah Knight (Moorfields Eye Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.177 AMACR Ivone Leong Gene: amacr has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.176 AMACR Ivone Leong Tag Q2_21_rating tag was added to gene: AMACR.
Tag Q2_21_NHS_review tag was added to gene: AMACR.
Retinal disorders v2.176 AMACR Ivone Leong Phenotypes for gene: AMACR were changed from Retinitis pigmentosa to Retinitis pigmentosa, MONDO:0019200; Alpha-methylacyl-CoA racemase deficiency, OMIM:614307
Retinal disorders v2.175 AMACR Ivone Leong Publications for gene: AMACR were set to PMID: 21686617; 20821052; 11861706; 10655068; 15249642; 23286897
Intestinal failure or congenital diarrhoea v1.35 TMPRSS15 Ivone Leong Classified gene: TMPRSS15 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.35 TMPRSS15 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.35 TMPRSS15 Ivone Leong Gene: tmprss15 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.34 TMPRSS15 Ivone Leong Tag Q2_21_rating tag was added to gene: TMPRSS15.
Intestinal failure or congenital diarrhoea v1.34 TMPRSS15 Ivone Leong Phenotypes for gene: TMPRSS15 were changed from Enterokinase deficiency, MIM# 226200 to Enterokinase deficiency, OMIM:226200
Intestinal failure or congenital diarrhoea v1.33 PLVAP Ivone Leong Classified gene: PLVAP as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.33 PLVAP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.33 PLVAP Ivone Leong Gene: plvap has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.32 PLVAP Ivone Leong Tag Q2_21_rating tag was added to gene: PLVAP.
Intestinal failure or congenital diarrhoea v1.32 PLVAP Ivone Leong Added comment: Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia.

PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia.

PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis.

PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Intestinal failure or congenital diarrhoea v1.32 PLVAP Ivone Leong Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Intestinal failure or congenital diarrhoea v1.31 PLVAP Ivone Leong Phenotypes for gene: PLVAP were changed from Diarrhoea 10, protein-losing enteropathy type, MIM# 618183 to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Intestinal failure or congenital diarrhoea v1.30 NEUROG3 Ivone Leong Classified gene: NEUROG3 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.30 NEUROG3 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.30 NEUROG3 Ivone Leong Gene: neurog3 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.29 NEUROG3 Ivone Leong Tag Q2_21_rating tag was added to gene: NEUROG3.
Intestinal failure or congenital diarrhoea v1.29 NEUROG3 Ivone Leong Phenotypes for gene: NEUROG3 were changed from Diarrhoea 4, malabsorptive, congenital, MIM# 610370 to Diarrhoea 4, malabsorptive, congenital, OMIM:610370
Structural eye disease v1.56 WNT2B Ivone Leong Classified gene: WNT2B as Amber List (moderate evidence)
Structural eye disease v1.56 WNT2B Ivone Leong Gene: wnt2b has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.55 WNT2B Ivone Leong Publications for gene: WNT2B were set to
Structural eye disease v1.54 WNT2B Ivone Leong Phenotypes for gene: WNT2B were changed from 29909964; 33526876 to Diarrhoea 9, OMIM:618168; microcornea; coloboma, MONDO:0001476
Structural eye disease v1.53 WNT2B Ivone Leong edited their review of gene: WNT2B: Changed publications: 29909964, 33526876; Changed phenotypes: Diarrhoea 9, OMIM:618168, microcornea, coloboma, MONDO:0001476
Structural eye disease v1.53 WNT2B Ivone Leong gene: WNT2B was added
gene: WNT2B was added to Structural eye disease. Sources: Literature
watchlist tags were added to gene: WNT2B.
Mode of inheritance for gene: WNT2B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WNT2B were set to 29909964; 33526876
Review for gene: WNT2B was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM but not Gene2Phenotype. This gene is also present on the Intestinal failure panel (Version 1.28).

Review submitted by Zornitza Stark on the Intestinal failure panel:
"Diarrhoea-9 is a form of neonatal-onset chronic diarrhoea characterized by an osmotic diarrhoea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption. Three probands from two unrelated families and functional data suggesting severe intestinal dysregulation due to decreased intestinal stem cell number and function. Borderline Green/Amber. Sources: Expert Review
Zornitza Stark (Australian Genomics), 4 Jan 2021"

PMID: 33526876 reports an additional unrelated case. Patient is of Haitian descent (previous cases described in PMID:29909964 are of Vietnamese and Kuwaiti origins). Patient has neonatal onset diarrhoea with metabolic acidosis and failure to thrive. Patient also has bilateral microcornea and corneal clouding. Patient also presented with ambiguous genitalia and diagnosed with 46,XX testicular DSD. The authors reviewed the clinical findings of the previous patients they had reported on (PMID:29909964) and found that the Kuwaiti patients had bilateral microcornea, corneal neovascularization and thick corneas (I-2), and bilateral iridocorneal adhesions, congenital cataract, and iris coloboma (I-3). The gonadal findings in the Haitian patient was not seen in any of the other affected patients.

As there are only 2 cases of patients with microcornea and coloboma this gene has been given an Amber rating.
Sources: Literature
Differences in sex development v2.46 WNT2B Ivone Leong gene: WNT2B was added
gene: WNT2B was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: WNT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT2B were set to 29909964; 33526876
Phenotypes for gene: WNT2B were set to Diarrhoea 9, OMIM:618168; 46,XX testicular disorder of sex development, MONDO:0100249
Review for gene: WNT2B was set to RED
Added comment: This gene is associated with a phenotype in OMIM but not Gene2Phenotype. This gene is also present on the Intestinal failure panel (Version 1.28).

Review submitted by Zornitza Stark on the Intestinal failure panel:
"Diarrhoea-9 is a form of neonatal-onset chronic diarrhoea characterized by an osmotic diarrhoea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption. Three probands from two unrelated families and functional data suggesting severe intestinal dysregulation due to decreased intestinal stem cell number and function. Borderline Green/Amber. Sources: Expert Review
Zornitza Stark (Australian Genomics), 4 Jan 2021"

PMID: 33526876 reports an additional unrelated case. Patient is of Haitian descent (previous cases described in PMID:29909964 are of Vietnamese and Kuwaiti origins). Patient has neonatal onset diarrhoea with metabolic acidosis and failure to thrive. Patient also has bilateral microcornea and corneal clouding. Patient also presented with ambiguous genitalia and diagnosed with 46,XX testicular DSD. The authors reviewed the clinical findings of the previous patients they had reported on (PMID:29909964) and found that the Kuwaiti patients had bilateral microcornea, corneal neovascularization and thick corneas (I-2), and bilateral iridocorneal adhesions, congenital cataract, and iris coloboma (I-3). The gonadal findings in the Haitian patient was not seen in any of the other affected patients.

As there is only 1 case, this gene has been added as Red on this panel.
Sources: Literature
Intestinal failure or congenital diarrhoea v1.28 WNT2B Ivone Leong Classified gene: WNT2B as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.28 WNT2B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.28 WNT2B Ivone Leong Gene: wnt2b has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.27 WNT2B Ivone Leong Tag Q2_21_rating tag was added to gene: WNT2B.
Intestinal failure or congenital diarrhoea v1.27 WNT2B Ivone Leong Added comment: Comment on publications: PMID: 33526876 reports an additional unrelated case. Patient is of Haitian descent (previous cases described in PMID:29909964 are of Vietnamese and Kuwaiti origins). Patient has neonatal onset diarrhoea with metabolic acidosis and failure to thrive. Patient also has bilateral microcornea and corneal clouding. Patient also presented with ambiguous genitalia and diagnosed with 46,XX testicular DSD.

The authors reviewed the clinical findings of the previous patients they had reported on (PMID:29909964) and found that the Kuwaiti patients had bilateral microcornea, corneal neovascularization and thick corneas (I-2), and bilateral iridocorneal adhesions, congenital cataract, and iris coloboma (I-3). The gonadal findings in the Haitian patient was not seen in any of the other affected patients.
Intestinal failure or congenital diarrhoea v1.27 WNT2B Ivone Leong Publications for gene: WNT2B were set to 29909964
Intestinal failure or congenital diarrhoea v1.26 WNT2B Ivone Leong Phenotypes for gene: WNT2B were changed from Diarrhoea 9, MIM# 618168 to Diarrhoea 9, OMIM:618168
Intestinal failure or congenital diarrhoea v1.25 TTC37 Ivone Leong Phenotypes for gene: TTC37 were changed from Trichohepatoenteric syndrome 1 222470 to Trichohepatoenteric syndrome 1, OMM:222470
Intestinal failure or congenital diarrhoea v1.24 STXBP2 Ivone Leong Phenotypes for gene: STXBP2 were changed from Hemophagocytic lymphohistiocytosis, familial, 5 613101 to Hemophagocytic lymphohistiocytosis, familial, 5, OMIM:613101
Intestinal failure or congenital diarrhoea v1.23 STX3 Ivone Leong Phenotypes for gene: STX3 were changed from Microvillus inclusion disease; congenital diarrheal disorder to Microvillus inclusion disease, MONDO:0009635; diarrheal disorder, MONDO:0001673
Intestinal failure or congenital diarrhoea v1.22 SPINT2 Ivone Leong Phenotypes for gene: SPINT2 were changed from congenital sodium diarrhea; Congenital tufting enteropathy to Diarrhea 3, secretory sodium, congenital, syndromic, OMIM:270420
Intestinal failure or congenital diarrhoea v1.21 SLC9A3 Ivone Leong Phenotypes for gene: SLC9A3 were changed from Congenital sodium diarrhea to Diarrhea 8, secretory sodium, congenital, OMM:616868
Intestinal failure or congenital diarrhoea v1.20 SLC26A3 Ivone Leong Phenotypes for gene: SLC26A3 were changed from Congenital chloride diarrhea to Diarrhea 1, secretory chloride, congenital, OMIM:214700
Intestinal failure or congenital diarrhoea v1.19 SKIV2L Ivone Leong Added comment: Comment on publications: 27537055 - a pathogenic variant (heterozygous state) in this gene was reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Intestinal failure or congenital diarrhoea v1.19 SKIV2L Ivone Leong Publications for gene: SKIV2L were set to 22444670; 27302973; 27537055 - a pathogenic variant (heterozygous state) in this gene was reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Intestinal failure or congenital diarrhoea v1.18 SKIV2L Ivone Leong Phenotypes for gene: SKIV2L were changed from Trichohepatoenteric syndrome 2 614602 to Trichohepatoenteric syndrome 2, OMIM:614602
Intestinal failure or congenital diarrhoea v1.17 MYO5B Ivone Leong Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, 251850 to Microvillus inclusion disease, OMIM:251850
Intestinal failure or congenital diarrhoea v1.16 GUCY2C Ivone Leong Phenotypes for gene: GUCY2C were changed from Familial Diarrhea 6 614616 to Familial Diarrhea 6, OMIM:614616
Intestinal failure or congenital diarrhoea v1.15 GUCY2C Ivone Leong Phenotypes for gene: GUCY2C were changed from Familial Diarrhea 6 614616 to Familial Diarrhea 6 614616
Intestinal failure or congenital diarrhoea v1.14 EPCAM Ivone Leong Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital 613217 to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Intestinal failure or congenital diarrhoea v1.13 DGAT1 Ivone Leong Phenotypes for gene: DGAT1 were changed from Congenital diarrheal disorder to Congenital diarrheal disorder; ?Diarrhea 7, protein-losing enteropathy type, OMIM:615863
Pancreatitis v2.10 CELA3B Ivone Leong Classified gene: CELA3B as Amber List (moderate evidence)
Pancreatitis v2.10 CELA3B Ivone Leong Added comment: Comment on list classification: New gene added by Miranda Durkie. This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 31369399. Other affected members of this large family could not be tested and therefore the genetic status of the affected individuals are unknown. The family also has a variant in FOXN1, as the gene is not expressed in the pancreas the authors hypothesised that the FOXN1 variant was not causative.

PMID: 33565216. Four patients with p.Arg90Leu (c.269G>T) were from cases with familial chronic pancreatitis and young cases with idiopathic chronic pancreatitis (2 each). The familial chronic pancreatitis cases each have an affected first‐degree relative who have not been analysed yet.

This gene has been added as an Amber gene and will be reviewed by the GMS specialist group to see if there is enough evidence to promote to Green status.
Pancreatitis v2.10 CELA3B Ivone Leong Gene: cela3b has been classified as Amber List (Moderate Evidence).
Pancreatitis v2.9 CELA3B Ivone Leong Tag Q2_21_rating tag was added to gene: CELA3B.
Tag Q2_21_NHS_review tag was added to gene: CELA3B.
Pancreatitis v2.9 CELA3B Ivone Leong Phenotypes for gene: CELA3B were changed from Chronic Pancreatitis; Diabetes; Pancreatic cancer to Chronic Pancreatitis, MONDO:0005003; diabetes mellitus (disease), MONDO:0005015; Pancreatic cancer
Pancreatitis v2.8 CELA3B Ivone Leong Publications for gene: CELA3B were set to
Intellectual disability v3.1003 NCKAP1 Zornitza Stark reviewed gene: NCKAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33157009; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1003 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 DPYS Zornitza Stark gene: DPYS was added
gene: DPYS was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: DPYS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DPYS were set to Dihydropyrimidinuria, MIM#222748
Review for gene: DPYS was set to GREEN
gene: DPYS was marked as current diagnostic
Added comment: Highly variable phenotype, but many have ID.
Sources: Expert Review
Intellectual disability v3.1003 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Intellectual disability v3.1003 B4GALT1 Zornitza Stark reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 30653653, 21920538; Phenotypes: Congenital disorder of glycosylation, type Iid, MIM#607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1003 AGO1 Zornitza Stark reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770, 28135719; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.411 ZNFX1 Boaz Palterer gene: ZNFX1 was added
gene: ZNFX1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ZNFX1 were set to mendelian susceptibility to mycobacterial disease; MSMD; monocytosis.
Penetrance for gene: ZNFX1 were set to unknown
Review for gene: ZNFX1 was set to RED
Added comment: Le Voyer et al. described two patients from two unrelated kindreds with homozygous LOF variants in the ZNFX1 gene associated with mendelian susceptibility to mycobacterial disease (MSMD) and monocytosis. ( https://www.pnas.org/content/118/15/e2102804118 )
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.411 SYK Boaz Palterer gene: SYK was added
gene: SYK was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SYK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYK were set to 33782605
Phenotypes for gene: SYK were set to immunodeficiency; hypogammaglobulinemia; multi-organ inflammatory disease
Penetrance for gene: SYK were set to unknown
Mode of pathogenicity for gene: SYK 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: SYK was set to AMBER
Added comment: Wang et al. identified six patients from unrelated kindreds with monoallelic SYK variants causing immunodeficiency and a multiorgan inflammatory disease. The variants were proven to be functionally gain-of-function. Functional GOF was confirmed in knock-in mouse experiments.
Sources: Literature
Fetal anomalies v1.637 PLD1 Suzanne Drury gene: PLD1 was added
gene: PLD1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD1 were set to 33645542
Phenotypes for gene: PLD1 were set to HP:0001654; HP:0001627; HP:0001638
Review for gene: PLD1 was set to GREEN
Added comment: PMID 33645542 identified 30 patients from 21 unrelated families of different ancestries with biallelic PLD1 variants. All 30 patients were diagnosed with severe congenital heart disease or
cardiomyopathy at the fetal or neonatal stage. PLD1 can also cause neonatal cardiomyopathy in the absence of congenital heart defects.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v1.13 RYR2 Matthew Edwards changed review comment from: On CGGL Royal Brompton DCM panel. Definitive ARVC/CPVT gene, appropriate for DCM panel due to possible phenotypic overlap. some evidence for exon 3 deletion specifically associated with DCM.; to: On CGGL Royal Brompton DCM panel. Definitive CPVT gene, appropriate for DCM panel due to possible phenotypic overlap as some evidence for exon 3 deletion specifically associated with DCM.
Ataxia and cerebellar anomalies - childhood onset v2.80 CLPP Sarah Leigh reviewed gene: CLPP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.80 CLPP Sarah Leigh Publications for gene: CLPP were set to 25254289
Ataxia and cerebellar anomalies - childhood onset v2.79 CLPP Sarah Leigh Phenotypes for gene: CLPP were changed from Perrault syndrome 3 OMIM:614129; Perrault syndrome 3 MONDO:0013588 to Perrault syndrome 3 OMIM:614129; Perrault syndrome 3 MONDO:0013588
Congenital disorders of glycosylation v2.66 SSR4 Sarah Leigh commented on gene: SSR4: GlyGen link updated April 2021: https://www.glygen.org/protein/P51571-1#Disease
Congenital disorders of glycosylation v2.66 SLC39A8 Sarah Leigh commented on gene: SLC39A8: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9C0K1-1#Disease
Congenital disorders of glycosylation v2.66 POMT2 Sarah Leigh commented on gene: POMT2: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9UKY4-1#Disease
Congenital disorders of glycosylation v2.66 POMGNT1 Sarah Leigh commented on gene: POMGNT1: GlyGen link updated April 2021: https://www.glygen.org/protein/Q8WZA1-1#Disease
Congenital disorders of glycosylation v2.66 POMT1 Sarah Leigh commented on gene: POMT1: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9Y6A1-1#Disease
Congenital disorders of glycosylation v2.66 PIGL Sarah Leigh commented on gene: PIGL: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9Y2B2-1#Disease
Congenital disorders of glycosylation v2.66 PIGO Sarah Leigh commented on gene: PIGO: GlyGen link updated April 2021: https://www.glygen.org/protein/Q8TEQ8-1#Disease
Congenital disorders of glycosylation v2.66 PIGA Sarah Leigh commented on gene: PIGA: GlyGen link updated April 2021: https://www.glygen.org/protein/P37287-1#Disease
Congenital disorders of glycosylation v2.66 PGM1 Sarah Leigh commented on gene: PGM1: GlyGen link updated April 2021: https://www.glygen.org/protein/P36871-1#Disease
Congenital disorders of glycosylation v2.66 PGAP2 Sarah Leigh commented on gene: PGAP2: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9UHJ9-1#Disease
Fetal anomalies v1.637 CLTC Suzanne Drury reviewed gene: CLTC: Rating: ; Mode of pathogenicity: None; Publications: PMID:33743358; Phenotypes: ; Mode of inheritance: None
Congenital disorders of glycosylation v2.66 LARGE1 Sarah Leigh commented on gene: LARGE1: GlyGen link updated April 2021: https://www.glygen.org/protein/O95461-1#Disease
Congenital disorders of glycosylation v2.66 FUT8 Sarah Leigh commented on gene: FUT8
Congenital disorders of glycosylation v2.66 FKTN Sarah Leigh commented on gene: FKTN: GlyGen link updated April 2021: https://www.glygen.org/protein/O75072-1#Disease
Congenital disorders of glycosylation v2.66 FKRP Sarah Leigh commented on gene: FKRP: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9H9S5-1#Disease
Congenital disorders of glycosylation v2.66 EXT2 Sarah Leigh commented on gene: EXT2: GlyGen link updated April 2021: https://www.glygen.org/protein/Q93063-1#Disease
Congenital disorders of glycosylation v2.66 EXT1 Sarah Leigh changed review comment from: GlyGen link: https://www.glygen.org/protein/Q16394-1#Disease; to: GlyGen link updated April 2021: https://www.glygen.org/protein/Q16394-1#Disease
Congenital disorders of glycosylation v2.66 EXT1 Sarah Leigh changed review comment from: Comment on phenotypes: Also associated with Chondrosarcoma 215300 ; to: Comment on phenotypes: Also associated with Chondrosarcoma 215300
Congenital disorders of glycosylation v2.66 EXT1 Sarah Leigh commented on gene: EXT1: GlyGen link: https://www.glygen.org/protein/Q16394-1#Disease
Congenital disorders of glycosylation v2.66 DPAGT1 Sarah Leigh commented on gene: DPAGT1: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9H3H5-1#Disease
Congenital disorders of glycosylation v2.66 CCDC115 Sarah Leigh commented on gene: CCDC115: GlyGen link updated April 2021: https://www.glygen.org/protein/Q96NT0-1#Disease
Congenital disorders of glycosylation v2.66 ATP6V0A2 Sarah Leigh commented on gene: ATP6V0A2: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9Y487-1#Disease
Congenital disorders of glycosylation v2.66 TMEM165 Sarah Leigh commented on gene: TMEM165: GlyGen link updated April 2021: https://www.glygen.org/protein/Q9HC07-1#Disease
Ataxia and cerebellar anomalies - childhood onset v2.78 CLPP Sarah Leigh Classified gene: CLPP as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.78 CLPP Sarah Leigh Gene: clpp has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.77 CLPP Sarah Leigh Classified gene: CLPP as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.77 CLPP Sarah Leigh Gene: clpp has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.76 CLPP Sarah Leigh Publications for gene: CLPP were set to 25254289
Ataxia and cerebellar anomalies - childhood onset v2.75 CLPP Sarah Leigh Phenotypes for gene: CLPP were changed from Perrault syndrome 3, MIM# 614129 to Perrault syndrome 3 OMIM:614129; Perrault syndrome 3 MONDO:0013588
Undiagnosed metabolic disorders v1.450 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5 256731 to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Intellectual disability v3.1003 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5, 256731; NEURONAL CEROID LIPOFUSCINOSIS TYPE 5 (CLN5) to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Likely inborn error of metabolism v2.106 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5, 256731 to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Retinal disorders v2.174 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Eye Disorders; Ceroid lipofuscinosis, neuronal, 5, 256731 to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Dystonia, chorea or related movement disorder, childhood onset v1.86 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5, 256731 to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
DDG2P v2.24 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from NEURONAL CEROID LIPOFUSCINOSIS TYPE 5 256731 to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Ataxia and cerebellar anomalies - childhood onset v2.74 CLN5 Sarah Leigh edited their review of gene: CLN5: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least ten variants reported in at least nine unrelated cases.
Ataxia is a feature of Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745; Changed rating: GREEN
Ataxia and cerebellar anomalies - childhood onset v2.74 CLN5 Sarah Leigh Tag Q2_21_rating tag was added to gene: CLN5.
Ataxia and cerebellar anomalies - childhood onset v2.74 CLN5 Sarah Leigh Classified gene: CLN5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.74 CLN5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.74 CLN5 Sarah Leigh Gene: cln5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.73 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5, MIM# 256731 to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Ataxia and cerebellar anomalies - childhood onset v2.72 BBS1 Sarah Leigh Tag Q2_21_rating tag was added to gene: BBS1.
Intellectual disability v3.1002 BBS1 Sarah Leigh Publications for gene: BBS1 were set to
Bardet Biedl syndrome v1.11 BBS1 Sarah Leigh Publications for gene: BBS1 were set to 12118255
Limb disorders v2.39 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Polydactyly; Bardet-Biedl syndrome 1 209900 to Polydactyly; Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Severe early-onset obesity v2.38 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Obesity; Bardet-Biedl syndrome 1, OMIM:209900 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Renal ciliopathies v1.41 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet Biedl syndrome 13; 268000; Bardet Biedl syndrome 1; Bardet Biedl syndrome 11 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Intellectual disability v3.1001 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet-Biedl syndrome 1, 209900; BARDET-BIEDL SYNDROME TYPE 1 (BBS1) to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Retinal disorders v2.173 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Eye Disorders; Retinitis pigmentosa; Bardet-Biedl syndrome 1, 209900 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
DDG2P v2.23 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from BARDET-BIEDL SYNDROME TYPE 1 209900 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Fetal anomalies v1.637 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from BARDET-BIEDL SYNDROME TYPE 1 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Unexplained young onset end-stage renal disease v1.16 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome type 1 209900 to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Skeletal dysplasia v2.87 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Polydactyly; Bardet-Biedl syndrome 1 209900 to Polydactyly; Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Bardet Biedl syndrome v1.10 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet-Biedl syndrome 1, 209900 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Ataxia and cerebellar anomalies - childhood onset v2.72 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet-Biedl syndrome 1, MIM#209900 to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Ataxia and cerebellar anomalies - childhood onset v2.71 BBS1 Sarah Leigh edited their review of gene: BBS1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in numerous unrelated cases.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.71 BBS1 Sarah Leigh Classified gene: BBS1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.71 BBS1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.71 BBS1 Sarah Leigh Gene: bbs1 has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.20 CFHR5 Sarah Leigh changed review comment from: PMID 22503529 reports a heterozygous 1bp insertion variant (rs565457964) in a child with Nephropathy due to CFHR5 deficiency OMIM:614809.; to: PMID 22503529 reports a heterozygous 1bp insertion variant (rs565457964) in a child with Nephropathy due to CFHR5 deficiency OMIM:614809 and persistent renal disease following a streptococcal infection. The variant was also seen in her unaffected mother and sister, which suggested that this variant is not sufficient to cause disease, but likely acts as a susceptibility factor for the development of glomerulonephritis.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.20 CFHR5 Sarah Leigh commented on gene: CFHR5
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.20 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.19 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961]
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.18 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.17 CFHR5 Sarah Leigh Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560
Additional findings health related - CNV analysis children v1.0 Eleanor Williams promoted panel to version 1.0
Additional findings health related - CNV analysis adult specific v1.0 Eleanor Williams promoted panel to version 1.0
Additional findings health related - children v1.0 Eleanor Williams promoted panel to version 1.0
Additional findings health related - adult specific v1.0 Eleanor Williams promoted panel to version 1.0
Gastrointestinal epithelial barrier disorders v1.60 ANO1 Arina Puzriakova Classified gene: ANO1 as Amber List (moderate evidence)
Gastrointestinal epithelial barrier disorders v1.60 ANO1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases and review of phenotype associated with variants in this gene.
Gastrointestinal epithelial barrier disorders v1.60 ANO1 Arina Puzriakova Gene: ano1 has been classified as Amber List (Moderate Evidence).
Familial melanoma v1.9 POT1 Arina Puzriakova Phenotypes for gene: POT1 were changed from Melanoma, cutaneous malignant, susceptibility to, 10, 615848 to Melanoma, cutaneous malignant, susceptibility to, 10, OMIM:615848
Familial melanoma v1.8 POT1 Arina Puzriakova Publications for gene: POT1 were set to 24686849; 24686846; 29523635; 30451293; 30586141; 32325837
Familial melanoma v1.7 POT1 Arina Puzriakova edited their review of gene: POT1: Changed publications: 24686849, 24686846, 29523635, 30451293, 30586141, 32325837, 32907878
Additional findings reproductive carrier status v1.0 Eleanor Williams promoted panel to version 1.0
Ataxia and cerebellar anomalies - childhood onset v2.70 ATP8A2 Sarah Leigh edited their review of gene: ATP8A2: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 21 variants reported in 17 unrelated cases with varying degrees of severity, together with supportive expression and functional studies (PMID 31612321).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1000 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 27679995; 30012219; 29531481; 29531481; 31612321
Hereditary ataxia, adult onset v2.35 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 29531481; 30012219; 31612321
Ataxia and cerebellar anomalies - childhood onset v2.70 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 29531481; 30012219; 31612321; 27679995
Ataxia and cerebellar anomalies - childhood onset v2.69 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 29531481; 30012219; 31612321
Intellectual disability v3.999 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 27679995; 30012219; 29531481
Hereditary ataxia, adult onset v2.34 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 31612321; 30012219
Ataxia and cerebellar anomalies - childhood onset v2.68 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 30012219; 31612321
Ataxia and cerebellar anomalies - childhood onset v2.67 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 31612321
Hereditary ataxia, adult onset v2.33 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 31612321
Ataxia and cerebellar anomalies - childhood onset v2.66 ATP8A2 Sarah Leigh Tag Q2_21_rating tag was added to gene: ATP8A2.
Ataxia and cerebellar anomalies - childhood onset v2.66 ATP8A2 Sarah Leigh Classified gene: ATP8A2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.66 ATP8A2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.66 ATP8A2 Sarah Leigh Gene: atp8a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.998 ATP8A2 Sarah Leigh Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104
Ataxia and cerebellar anomalies - childhood onset v2.65 ATP8A2 Sarah Leigh Phenotypes for gene: ATP8A2 were changed from Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268 to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104
Hereditary ataxia, adult onset v2.32 ATP8A2 Sarah Leigh Phenotypes for gene: ATP8A2 were changed from Cerebellar ataxia, mental retardation and dysequilibirum syndrome 4 to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104
Hereditary ataxia, adult onset v2.31 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528
Ataxia and cerebellar anomalies - childhood onset v2.64 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to PMID: 22892528
Ataxia and cerebellar anomalies - childhood onset v2.63 ATCAY Sarah Leigh reviewed gene: ATCAY: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.215 ATCAY Sarah Leigh reviewed gene: ATCAY: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.997 SPEN Arina Puzriakova Publications for gene: SPEN were set to 33057194
Intellectual disability v3.996 SPEN Arina Puzriakova Classified gene: SPEN as Amber List (moderate evidence)
Intellectual disability v3.996 SPEN Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next review - sufficient cases (>20) with truncating SPEN variants and GDD/ID of relevant severity to this panel.
Intellectual disability v3.996 SPEN Arina Puzriakova Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.995 SPEN Arina Puzriakova Tag Q2_21_rating tag was added to gene: SPEN.
Dystonia, chorea or related movement disorder, childhood onset v1.85 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.85 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.84 MED27 Arina Puzriakova gene: MED27 was added
gene: MED27 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Q2_21_rating tags were added to gene: MED27.
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Review for gene: MED27 was set to GREEN
Added comment: MED27 is currently not associated with any phenotype in OMIM (last edited on 08/03/2012), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'MED27-related neurodevelopmental disorder'

- PMID: 33443317 (2021) - 16 individuals from 11 families with a neurodevelopmental syndrome characterised by mild to profound GDD/ID (14/14), axial hypotonia (14/15), distal spasticity and dystonic movements (13/15), cerebellar hypoplasia (12/14), cataracts (10/15), epilepsy (9/15), and microcephaly (4/14). Exome sequencing revealed biallelic variants in the MED27 gene, including 3 recurrent variants found in 2 or more families with different background.

Overall sufficient (>3) unrelated cases for inclusion if phenotypes are considered to be within the scope of this panel - most individuals presented dystonic movements, but only 2 sibs experienced generalised dystonia.
Sources: Literature
Early onset or syndromic epilepsy v2.315 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.315 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.314 MED27 Arina Puzriakova gene: MED27 was added
gene: MED27 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: MED27.
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Review for gene: MED27 was set to GREEN
Added comment: MED27 is currently not associated with any phenotype in OMIM (last edited on 08/03/2012), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'MED27-related neurodevelopmental disorder'

- PMID: 33443317 (2021) - 16 individuals from 11 families with a neurodevelopmental syndrome characterised by mild to profound GDD/ID (14/14), axial hypotonia (14/15), distal spasticity and dystonic movements (13/15), cerebellar hypoplasia (12/14), cataracts (10/15), epilepsy (9/15), and microcephaly (4/14). Age of seizure onset ranged from 20 days to 5 years and seizure types were varied. Epilepsy was drug-resistant in 3/9 patients. Exome sequencing revealed biallelic variants in the MED27 gene, including 3 recurrent variants found in 2 or more families with different background.

Overall sufficient (>3) unrelated cases with epilepsy in patients with MED27 variants for inclusion on this panel as diagnostic-grade (Green).
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.68 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.68 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.67 MED27 Arina Puzriakova gene: MED27 was added
gene: MED27 was added to Cataracts. Sources: Literature
Q2_21_rating tags were added to gene: MED27.
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Review for gene: MED27 was set to GREEN
Added comment: MED27 is currently not associated with any phenotype in OMIM (last edited on 08/03/2012), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'MED27-related neurodevelopmental disorder'

- PMID: 33443317 (2021) - 16 individuals from 11 families with a neurodevelopmental syndrome characterised by mild to profound GDD/ID (14/14), axial hypotonia (14/15), distal spasticity and dystonic movements (13/15), cerebellar hypoplasia (12/14), epilepsy (9/15), and microcephaly (4/14). Cataracts were present in 10/15 patients, with four reporting mature cataracts, and 2 sibs had posterior cataracts. Exome sequencing revealed biallelic variants in the MED27 gene, including 3 recurrent variants found in 2 or more families with different background.

Overall sufficient (>3) unrelated cases with cataracts in patients in MED27 variants for inclusion on this panel as diagnostic-grade (Green).
Sources: Literature
Intellectual disability v3.995 MED27 Arina Puzriakova Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Intellectual disability v3.994 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Intellectual disability v3.994 MED27 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next review - at least 11 unrelated families reported with MED27 variants presenting overlapping phenotypes that include ID of relevant severity to this panel.
Intellectual disability v3.994 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.993 MED27 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MED27.
Intellectual disability v3.993 MED27 Arina Puzriakova reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: 33443317; Phenotypes: Intellectual disability, Axial hypotonia, Spasticity, Dystonia, Cerebellar hypoplasia, Cataracts, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.30 ATCAY Sarah Leigh Publications for gene: ATCAY were set to 29449188; 14556008; 23226316
Hereditary ataxia v1.215 ATCAY Sarah Leigh Publications for gene: ATCAY were set to 29449188; 14556008; 23226316
Ataxia and cerebellar anomalies - childhood onset v2.63 ATCAY Sarah Leigh Publications for gene: ATCAY were set to 29449188; 14556008; 23226316
Hereditary ataxia, adult onset v2.29 ATCAY Sarah Leigh Phenotypes for gene: ATCAY were changed from Cerebellar Ataxia, Cayman type; Cayman Ataxia, 601238; Ataxia, cerebellar, Cayman type to Ataxia, cerebellar, Cayman type OMIM:601238; Cayman type cerebellar ataxia MONDO:0011025
Hereditary ataxia, adult onset v2.28 ATCAY Sarah Leigh Publications for gene: ATCAY were set to
Hereditary ataxia v1.214 ATCAY Sarah Leigh Publications for gene: ATCAY were set to
Ataxia and cerebellar anomalies - childhood onset v2.62 ATCAY Sarah Leigh Publications for gene: ATCAY were set to 29449188; 14556008
Hereditary ataxia v1.213 ATCAY Sarah Leigh Phenotypes for gene: ATCAY were changed from Ataxia, cerebellar, Cayman type ; Cerebellar Ataxia, Cayman type to Ataxia, cerebellar, Cayman type OMIM:601238; Cayman type cerebellar ataxia MONDO:0011025
Ataxia and cerebellar anomalies - childhood onset v2.61 ATCAY Sarah Leigh Phenotypes for gene: ATCAY were changed from Ataxia, cerebellar, Cayman type; Cerebellar Ataxia, Cayman type to Ataxia, cerebellar, Cayman type OMIM:601238; Cayman type cerebellar ataxia MONDO:0011025
Ataxia and cerebellar anomalies - childhood onset v2.60 ATCAY Sarah Leigh Publications for gene: ATCAY were set to
Severe microcephaly v2.110 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
Severe microcephaly v2.110 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.109 EIF5A Arina Puzriakova gene: EIF5A was added
gene: EIF5A was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: EIF5A.
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: EIF5A is currently not associated with any phenotype in OMIM (last edited on 18/07/2019), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'EIF5A-related craniofacial-neurodevelopmental disorder'

- PMID: 33547280 (2021) reports 7 unrelated individuals with different de novo heterozygous variants in the EIF5A gene. Microcephaly was evident at birth in 3/5 individuals, and assessments in later life indicated microcephaly in 5/7 cases (HC ranging between -1.94 and -7.47 SD). Other features include DD/ID and craniofacial dysmorphism, including micrognathia. Supportive functional data included.

Overall sufficient (>3) unrelated cases of microcephaly in patients with EIF5A variants, for inclusion on this panel.
Sources: Literature
Intellectual disability v3.993 EIF5A Arina Puzriakova Tag Q2_21_rating tag was added to gene: EIF5A.
Intellectual disability v3.993 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
Intellectual disability v3.993 EIF5A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next review - PMID: 33547280 (2021) reports 7 unrelated individuals with different de novo heterozygous variants in the EIF5A gene. All were affected by variable degrees of DD and/or ID, mostly within the moderate severity range. Other features such as microcephaly and craniofacial dysmorphism were prominent but overall, the phenotype is best represented by this panel. Supportive functional data included.

EIF5A is currently not associated with any phenotype in OMIM (last edited on 18/07/2019), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'EIF5A-related craniofacial-neurodevelopmental disorder'
Intellectual disability v3.993 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Inherited bleeding disorders v1.159 ARPC1B Arina Puzriakova Phenotypes for gene: ARPC1B were changed from Platelet disorder; Thrombocytopenia and Immune Deficiency to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718; Combined immune deficiency with or without thrombocytopenia; Inflammatory predisposition
COVID-19 research v1.77 ARPC1B Arina Puzriakova Phenotypes for gene: ARPC1B were changed from inflammatory predisposition; Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718; Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching; Immunodeficiency with thrombocytopenia; Combined immunodeficiencies with associated or syndromic features; Thrombocytopenia & Immune Deficiency to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718; Combined immune deficiency with or without thrombocytopenia; Inflammatory predisposition
Bleeding and platelet disorders v1.26 ARPC1B Arina Puzriakova Phenotypes for gene: ARPC1B were changed from 617718 Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718
Cytopenia - NOT Fanconi anaemia v1.37 ARPC1B Arina Puzriakova Phenotypes for gene: ARPC1B were changed from Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718 to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718
Primary immunodeficiency or monogenic inflammatory bowel disease v2.411 ARPC1B Arina Puzriakova Publications for gene: ARPC1B were set to 28368018; 29127144; 27965109
Primary immunodeficiency or monogenic inflammatory bowel disease v2.410 ARPC1B Arina Puzriakova Phenotypes for gene: ARPC1B were changed from Thrombocytopenia & Immune Deficiency; Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718; inflammatory predisposition; Immunodeficiency with thrombocytopenia; Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching; Combined immunodeficiencies with associated or syndromic features to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718; Combined immune deficiency with or without thrombocytopenia; Inflammatory predisposition
Primary immunodeficiency or monogenic inflammatory bowel disease v2.409 MR1 Arina Puzriakova Classified gene: MR1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.409 MR1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single patient described in PMID: 32709702 who presented immunodeficiency and a homozygous MR1 variant (c.92G>A, p.Arg31His) supported by some functional data. Rating Red, awaiting further evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.409 MR1 Arina Puzriakova Gene: mr1 has been classified as Red List (Low Evidence).
Severe microcephaly v2.108 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, 613078 to Nijmegen breakage syndrome-like disorder, OMIM:613078
Severe microcephaly v2.107 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520; 32212377
Severe microcephaly v2.106 RAD50 Arina Puzriakova Classified gene: RAD50 as Amber List (moderate evidence)
Severe microcephaly v2.106 RAD50 Arina Puzriakova Added comment: Comment on list classification: There are now a total of 3 unrelated cases (PMIDs: 19409520; 32212377; 33378670) with a RAD50‐related syndrome including microcephaly. This therefore reaches the threshold for promotion of this gene to Green status at the next review (removed 'watchlist' tag and added 'Q2_21_rating' tag)
Severe microcephaly v2.106 RAD50 Arina Puzriakova Gene: rad50 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.105 RAD50 Arina Puzriakova Tag watchlist was removed from gene: RAD50.
Tag Q2_21_rating tag was added to gene: RAD50.
Severe microcephaly v2.105 RAD50 Arina Puzriakova edited their review of gene: RAD50: Added comment: - PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects (including microcephaly), who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.; Changed rating: GREEN; Changed publications: 19409520, 32212377, 33378670; Changed phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.992 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, 613078 to Nijmegen breakage syndrome-like disorder, OMIM:613078
Intellectual disability v3.991 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520; 32212377
Intellectual disability v3.990 RAD50 Arina Puzriakova edited their review of gene: RAD50: Added comment: - PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects, who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.

This is the third case published with biallelic variants in the RAD50 gene. Although authors report 'developmental defects', it is unclear whether this individual displayed cognitive impairment. Therefore, maintaining the Red gene rating on this panel.; Changed rating: RED; Changed publications: 19409520, 32212377, 33378670; Changed phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.408 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from bone marrow failure; immunodeficiency; developmental defect to Nijmegen breakage syndrome-like disorder, OMIM:613078; Bone marrow failure; Immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.407 RAD50 Arina Puzriakova Classified gene: RAD50 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.407 RAD50 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Of the three total patients reported to date with biallelic variants in this gene, only one exhibited bone marrow failure and immunodeficiency (PMID: 33378670). Therefore rating Red on this panel until further cases are reported which indicate that RAD50 variants contribute to immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.407 RAD50 Arina Puzriakova Gene: rad50 has been classified as Red List (Low Evidence).
Neurotransmitter disorders v1.9 ALDH5A1 Sarah Leigh Classified gene: ALDH5A1 as Green List (high evidence)
Neurotransmitter disorders v1.9 ALDH5A1 Sarah Leigh Gene: aldh5a1 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.59 ALDH5A1 Sarah Leigh edited their review of gene: ALDH5A1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in numerous cases, together with supportive functional evidence and mouse model.; Changed rating: GREEN
Neurotransmitter disorders v1.8 ALDH5A1 Sarah Leigh edited their review of gene: ALDH5A1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in numerous cases, together with supportive functional evidence and mouse model.; Changed rating: GREEN
Neurotransmitter disorders v1.8 ALDH5A1 Sarah Leigh Tag Q2_21_rating tag was added to gene: ALDH5A1.
Neurotransmitter disorders v1.8 ALDH5A1 Sarah Leigh Classified gene: ALDH5A1 as Amber List (moderate evidence)
Neurotransmitter disorders v1.8 ALDH5A1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Neurotransmitter disorders v1.8 ALDH5A1 Sarah Leigh Gene: aldh5a1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.59 ALDH5A1 Sarah Leigh Classified gene: ALDH5A1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.59 ALDH5A1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.59 ALDH5A1 Sarah Leigh Gene: aldh5a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.990 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to
Likely inborn error of metabolism v2.105 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to 27604308
Early onset or syndromic epilepsy v2.313 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to
Likely inborn error of metabolism v2.104 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Intellectual disability v3.989 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency, 271980; SUCCINATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Early onset or syndromic epilepsy v2.312 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency 271980 to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Neurotransmitter disorders v1.7 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency, MIM# 271980 to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Ataxia and cerebellar anomalies - childhood onset v2.58 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to 14635103
Intellectual disability v3.988 GNB1 Arina Puzriakova Phenotypes for gene: GNB1 were changed from Intellectual disability; developmental delay; Global developmental delay to Mental retardation, autosomal dominant 42, OMIM:616973
Intellectual disability v3.987 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Developmental regression; Seizures; Ataxia; Intellectual disability to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Hereditary ataxia, adult onset v2.27 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to
Intellectual disability v3.986 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to 30100084
Early onset or syndromic epilepsy v2.311 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to 30100084
Early onset or syndromic epilepsy v2.310 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Intellectual disability, cerebellar atrophy, ataxia and epilepsy to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
DDG2P v2.22 ADPRHL2 Sarah Leigh Added comment: Comment on phenotypes: Degenerative Pediatric Stress Induced Epileptic Ataxia Syndrome;Neurodegeneration with Developmental Delay Ataxia and Axonal Neuropathy
DDG2P v2.22 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Degenerative Pediatric Stress Induced Epileptic Ataxia Syndrome; Neurodegeneration with Developmental Delay Ataxia and Axonal Neuropathy to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Ataxia and cerebellar anomalies - childhood onset v2.57 ADPRHL2 Sarah Leigh Classified gene: ADPRHL2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.57 ADPRHL2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - childhood onset v2.57 ADPRHL2 Sarah Leigh Gene: adprhl2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.56 ADPRHL2 Sarah Leigh edited their review of gene: ADPRHL2: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 8 variants reported in 8 unrelated cases, together with supportive fuctional studies and a Drosophila paralog where a loss of Parg resulted in lethality on oxidative challenge that was rescued by human ADPRHL2.; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v2.406 RAD50 Arina Puzriakova reviewed gene: RAD50: Rating: RED; Mode of pathogenicity: None; Publications: 33378670; Phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism v1.32 SPRY4 Ivone Leong Publications for gene: SPRY4 were set to 23643382
Ataxia and cerebellar anomalies - childhood onset v2.56 ADPRHL2 Sarah Leigh commented on gene: ADPRHL2
Hypogonadotropic hypogonadism v1.31 SPRY4 Ivone Leong Tag Q2_21_expert_review tag was added to gene: SPRY4.
Hypogonadotropic hypogonadism v1.31 SPRY4 Ivone Leong Classified gene: SPRY4 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism v1.31 SPRY4 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber.

PMID:23643382 - 14 unrelated cases had variants in SPRY4, 3 cases had variants in other genes (DUSP6 and FGFR1).

PMID: 32389901 - 1 cases had variants in SPRY4 and PLXNA1.

Based on the available evidence, this variants in this gene may contribute to disease. Therefore this gene has been promoted from Red to Amber.
Hypogonadotropic hypogonadism v1.31 SPRY4 Ivone Leong Gene: spry4 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.56 ADPRHL2 Sarah Leigh Tag new-gene-name tag was added to gene: ADPRHL2.
Ataxia and cerebellar anomalies - childhood onset v2.56 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Hereditary ataxia, adult onset v2.26 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Neurodegeneration, childhood-onset, stress-induced with variable ataxia and seizures, 618170 to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Ataxia and cerebellar anomalies - childhood onset v2.55 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170 to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170
Hypogonadotropic hypogonadism v1.30 SPRY4 Ivone Leong Phenotypes for gene: SPRY4 were changed from Hypogonadotropic hypogonadism 17 with or without anosmia 615266 to Hypogonadotropic hypogonadism 17 with or without anosmia, OMIM:615266
Hypogonadotropic hypogonadism (GMS) v1.42 IL17RD Ivone Leong edited their review of gene: IL17RD: Added comment: In addition to the review by Zornitza Stark (Australian Genomics), PMID: 23643382 states the following:

"Collectively, these data indicate that IL17RD mutations are strongly associated with KS and hearing loss; however, one allelic defect is most likely not sufficient, meaning that additional affected alleles in the same and/or other genes must be present to create the phenotype of KS with hearing loss."; Changed rating: AMBER
Hypogonadotropic hypogonadism (GMS) v1.42 IL17RD Ivone Leong Tag Q2_21_expert_review tag was added to gene: IL17RD.
Hypogonadotropic hypogonadism (GMS) v1.42 DUSP6 Ivone Leong Classified gene: DUSP6 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.42 DUSP6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype.

PMID: 23643382 - 5 cases with variants in DUSP6 (3 of these cases have variants in other genes FGFR1 and SPRY4).

PMID: 32389901 - 6 cases with variants in DUSP6 (1 case also has variants in CCDC141).

Based on the available evidence this gene has been given an Amber rating and will be reviewed by the GMS specialist group.
Hypogonadotropic hypogonadism (GMS) v1.42 DUSP6 Ivone Leong Gene: dusp6 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.41 DUSP6 Ivone Leong Tag Q2_21_expert_review tag was added to gene: DUSP6.
Hypogonadotropic hypogonadism (GMS) v1.41 FGF17 Ivone Leong Classified gene: FGF17 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.41 FGF17 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype.

PMID: 23643382 identfied 3 cases with variants in the FGF17 gene. However, 1 of these cases have variants in other genes as well (FLRT3, HS6ST1 and FGFR1).

Based on the available evidence variants in this gene contribute to disease with variable penetrance. This gene has been given an Amber rating until further evidence is available.
Hypogonadotropic hypogonadism (GMS) v1.41 FGF17 Ivone Leong Gene: fgf17 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.40 FGF17 Ivone Leong Tag Q2_21_expert_review tag was added to gene: FGF17.
Skeletal dysplasia v2.86 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Skeletal dysplasia v2.85 SCUBE3 Sarah Leigh edited their review of gene: SCUBE3: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; Changed rating: GREEN
Skeletal dysplasia v2.85 SCUBE3 Sarah Leigh Classified gene: SCUBE3 as Amber List (moderate evidence)
Skeletal dysplasia v2.85 SCUBE3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal dysplasia v2.85 SCUBE3 Sarah Leigh Gene: scube3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.84 SCUBE3 Sarah Leigh Tag Q2_21_rating tag was added to gene: SCUBE3.
Skeletal dysplasia v2.84 SCUBE3 Sarah Leigh Publications for gene: SCUBE3 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.406 POU2AF1 Arina Puzriakova Classified gene: POU2AF1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.406 POU2AF1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single patient described in PMID: 33571536 with agammaglobulinemia and a homozygous POU2AF1 variant (c.233delC, p.Thr78Lysfs∗63) supported by functional data. Rating Red, awaiting further evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.406 POU2AF1 Arina Puzriakova Gene: pou2af1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.405 GIMAP5 Arina Puzriakova Tag treatable tag was added to gene: GIMAP5.
Tag watchlist tag was added to gene: GIMAP5.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.405 GIMAP5 Arina Puzriakova Classified gene: GIMAP5 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.405 GIMAP5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. 4 unrelated families with an immunodeficiency disorder and difference biallelic LoF variants in the GIMAP5 gene. Clinical improvement in Gimap5-deficient mice and a human patient was observed following treatment with rapamycin (mTORC1 inhibitor)

Although there are sufficient cases with a relevant phenotype, rating this gene Amber while pending publication of the Park 2021 article, as information can change from the initial bioRxiv upload to peer-reviewed publication. Added 'watchlist' tag and will re-curate when the paper is published.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.405 GIMAP5 Arina Puzriakova Gene: gimap5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.404 MAP1LC3B2 Arina Puzriakova Classified gene: MAP1LC3B2 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.404 MAP1LC3B2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single patient described in PMID:33310865 with recurrent herpes simplex virus 2-induced lymphocytic Mollaret's meningitis, and a MAP1LC3B2 variant (c.325C>A) supported by functional data. Rating Red, awaiting further evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.404 MAP1LC3B2 Arina Puzriakova Gene: map1lc3b2 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.403 ATG4A Arina Puzriakova Classified gene: ATG4A as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.403 ATG4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single patient described in PMID:33310865 with recurrent herpes simplex virus 2-induced lymphocytic Mollaret's meningitis, and a ATG4A variant (c.268C>A) supported by functional data. Rating Red, awaiting further evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.403 ATG4A Arina Puzriakova Gene: atg4a has been classified as Red List (Low Evidence).
Bleeding and platelet disorders v1.25 MAST2 Arina Puzriakova Classified gene: MAST2 as Red List (low evidence)
Bleeding and platelet disorders v1.25 MAST2 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single family reported at this time (PMID:33465109)
Bleeding and platelet disorders v1.25 MAST2 Arina Puzriakova Gene: mast2 has been classified as Red List (Low Evidence).
Bleeding and platelet disorders v1.24 MAST2 Arina Puzriakova Phenotypes for gene: MAST2 were changed from Thrombophilia; venous thrombosis to Venous thromboembolism; Thrombophilia
Thrombophilia with a likely monogenic cause v1.19 MAST2 Arina Puzriakova gene: MAST2 was added
gene: MAST2 was added to Thrombophilia. Sources: Literature
Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST2 were set to 33465109
Phenotypes for gene: MAST2 were set to Venous thromboembolism; Thrombophilia
Review for gene: MAST2 was set to RED
Added comment: - PMID: 33465109 (2021) - Single missense variant (p.Arg89Gln) identified in a French family with venous thrombosis and thrombophilia. Missense variant reviewed by in silico tools only. MAST2 knockdown was shown to affect regulation of TFP1 and SERPINE1 gene expression, known to regulate the haemostatic properties of endothelial cells. RNAi of MAST2 followed by RNAseq also showed expression changes in many other downstream targets.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v1.36 RPL27 Arina Puzriakova commented on gene: RPL27
Cytopenia - NOT Fanconi anaemia v1.36 RPL27 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: RPL27.
Severe microcephaly v2.105 PRIM1 Arina Puzriakova gene: PRIM1 was added
gene: PRIM1 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: PRIM1.
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to AMBER
Added comment: PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype.

- PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Retinal disorders v2.172 AMACR Hannah Knight gene: AMACR was added
gene: AMACR was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: AMACR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMACR were set to PMID: 21686617; 20821052; 11861706; 10655068; 15249642; 23286897
Phenotypes for gene: AMACR were set to Retinitis pigmentosa
Penetrance for gene: AMACR were set to Complete
Mode of pathogenicity for gene: AMACR was set to Other
Review for gene: AMACR was set to GREEN
Added comment: Only three reported mutations to our knowledge:
c.154T>C; p.Ser52Pro (most common)
c.367G>A; p.Asp123Asn
c.559G>A; p.Gly187Arg

For some patients, the retinal disorder can be the first manifestation of the condition, prior to developing neurological symptoms. We believe this gene should be on the retinal disorders panel to enable a quicker diagnosis and pre-emptive referrals to neurology.
Sources: Literature
Intellectual disability v3.985 TMPRSS9 Arina Puzriakova Added comment: Comment on mode of inheritance: Rating this gene Red as second case is based on unpublished results, but with a watchlist tag as new data on this gene-disease association may become available soon.
Intellectual disability v3.985 TMPRSS9 Arina Puzriakova Mode of inheritance for gene: TMPRSS9 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.984 TMPRSS9 Arina Puzriakova gene: TMPRSS9 was added
gene: TMPRSS9 was added to Intellectual disability. Sources: Other
watchlist tags were added to gene: TMPRSS9.
Mode of inheritance for gene: TMPRSS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS9 were set to 31943016
Phenotypes for gene: TMPRSS9 were set to Progressive intellectual and neurological deterioration; Global developmental delay; Intellectual disability; Autism; Epilepsy
Review for gene: TMPRSS9 was set to RED
Added comment: TMPRSS9 is currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 31943016 (2020) - Single female subject with compound heterozygous nonsense variants (paternal: c.286C>T, p.R96*; maternal: c.1267C>T; p.R423*) in TMPRSS9. Early childhood development was normal until 2.5 years of age when she experienced profound developmental regression, including speech, social interaction and motor skills, resulting in ASD and profound ID. Knockout mice showed decreased social interest and recognition, and additionally borderline recognition memory deficit in aged female mice.

- Conference poster (Genomics of Rare Disease 2021) - 'ZOEMBA: combining metabolomics and genomics data to solve the unsolved' by Oud et al, United for Metabolic Diseases (UMD), Netherlands -
Trio WES revealed compound heterozygous variants (paternal: c.143-1G>A, p.?; maternal: c.1864G>A; p.V622M) in the TMPRSS9 gene in a female proband with GDD, PIND, aggression, autism and epilepsy. The individual was recruited on the basis of 'suspicion of an inherited metabolic disorder and extensive genetic and metabolic work-up with no diagnosis'.
Sources: Other
Intellectual disability v3.983 DDB1 Arina Puzriakova Classified gene: DDB1 as Amber List (moderate evidence)
Intellectual disability v3.983 DDB1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next review - sufficient unrelated cases (8) presenting consistent features primarily characterised by ID/DD and hypotonia, supported by functional data (PMID:33743206)
Intellectual disability v3.983 DDB1 Arina Puzriakova Gene: ddb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.982 DDB1 Arina Puzriakova changed review comment from: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature; to: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.

Variants in other CRL4 complex components, such as CUL4B (MIM# 300304) and PHIP (MIM# 612870), have been shown to cause overlapping phenotypes consisting of syndromic ID with hypotonia and obesity.
Sources: Literature
Intellectual disability v3.982 DDB1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DDB1.
Intellectual disability v3.982 DDB1 Arina Puzriakova gene: DDB1 was added
gene: DDB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDB1 were set to 33743206
Phenotypes for gene: DDB1 were set to Intellectual disability
Review for gene: DDB1 was set to GREEN
Added comment: - PMID: 33743206 (2021) - 8 unrelated individuals with de novo variants in DDB1, including one recurrent variant in four individuals (c.637G>A, p.Glu213Lys) and two different substitutions at the same amino acid residue (p.Arg188Trp and p.Arg188Gln). Clinical features were consistent and include hypotonia (7/8) and mild-moderate developmental delay or intellectual disability (8/8) and similar facial gestalt. Brachydactyly was common and most noticeable in the feet (6/8), and two individuals had cutaneous toe syndactyly. All three older individuals had a BMI in the obese range for their age. Functional studies using patient-derived lymphoblasts showed altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage.
Sources: Literature
Intellectual disability v3.981 GSPT2 Arina Puzriakova Tag watchlist tag was added to gene: GSPT2.
Intellectual disability v3.981 GSPT2 Arina Puzriakova commented on gene: GSPT2
Early onset or syndromic epilepsy v2.309 NEUROD2 Arina Puzriakova Publications for gene: NEUROD2 were set to 30323019; 16504944
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Changed publications: 16504944, 30323019, 33438828
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova reviewed gene: NEUROD2: Rating: ; Mode of pathogenicity: None; Publications: 30323019, 16504944; Phenotypes: Developmental and epileptic encephalopathy 72, OMIM:618374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova Phenotypes for gene: NEUROD2 were changed from Epileptic encephalopathy, early infantile, 72, MIM# 618374 to Developmental and epileptic encephalopathy 72, OMIM:618374
Dystonia, chorea or related movement disorder, adult onset v1.113 YY1 Arina Puzriakova Phenotypes for gene: YY1 were changed from Gabriele-de Vries syndrome to Gabriele-de Vries syndrome, OMIM:617557
Dystonia, chorea or related movement disorder, adult onset v1.112 VAMP2 Arina Puzriakova Publications for gene: VAMP2 were set to
Dystonia, chorea or related movement disorder, adult onset v1.111 VAMP2 Arina Puzriakova Mode of inheritance for gene: VAMP2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dystonia, chorea or related movement disorder, adult onset v1.110 VAMP2 Arina Puzriakova Phenotypes for gene: VAMP2 were changed from to Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements, OMIM:618760
Dystonia, chorea or related movement disorder, adult onset v1.109 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from ?{Parkinson disease 5, susceptibility to}; ?{Parkinson disease 5, susceptibility to}, 613643; Spastic paraplegia 79, autosomal recessive, 615491 to {?Parkinson disease 5, susceptibility to}, OMIM:613643
Dystonia, chorea or related movement disorder, adult onset v1.108 TAF1 Arina Puzriakova Phenotypes for gene: TAF1 were changed from Dystonia-Parkinsonism, X-linked, 314250; SVA retrotransposon insertion Dystonia-Parkinsonism, X-linked, 314250; (NB complex mutation) to Dystonia-Parkinsonism, X-linked, OMIM:314250
Dystonia, chorea or related movement disorder, adult onset v1.107 PDE2A Arina Puzriakova Phenotypes for gene: PDE2A were changed from to Intellectual developmental disorder with paroxysmal dyskinesia or seizures, OMIM:619150
Dystonia, chorea or related movement disorder, adult onset v1.106 PDE2A Arina Puzriakova Mode of inheritance for gene: PDE2A was changed from to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, adult onset v1.105 CHCHD2 Arina Puzriakova Phenotypes for gene: CHCHD2 were changed from 616710; Parkinson disease 22, autosomal dominant to Parkinson disease 22, autosomal dominant, OMIM:616710
Dystonia, chorea or related movement disorder, adult onset v1.104 AUH Arina Puzriakova Phenotypes for gene: AUH were changed from 3-methylglutaconic aciduria, type I, 250950; Dystonia to 3-methylglutaconic aciduria, type I, OMIM:250950; Dystonia
Dystonia, chorea or related movement disorder, adult onset v1.103 ARX Arina Puzriakova Phenotypes for gene: ARX were changed from Partington Syndrome, OMIM:300382 to Partington Syndrome, OMIM:309510
Dystonia, chorea or related movement disorder, adult onset v1.102 ARX Arina Puzriakova Phenotypes for gene: ARX were changed from Partington Syndrome, 300382; Dystonia to Partington Syndrome, OMIM:300382
Dystonia, chorea or related movement disorder, adult onset v1.101 ARSA Arina Puzriakova Mode of inheritance for gene: ARSA was changed from to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, adult onset v1.100 ARSA Arina Puzriakova Phenotypes for gene: ARSA were changed from Metachromatic leukodystrophy, 250100; Dystonia to Metachromatic leukodystrophy, OMIM:250100
Dystonia, chorea or related movement disorder, adult onset v1.99 XPR1 Arina Puzriakova Phenotypes for gene: XPR1 were changed from Basal ganglia calcification, idiopathic, 6 616413 to Basal ganglia calcification, idiopathic, 6, OMIM:616413
Dystonia, chorea or related movement disorder, adult onset v1.98 WDR45 Arina Puzriakova Phenotypes for gene: WDR45 were changed from Neurodegeneration with brain iron accumulation 5 300894; Dystonia; beta-propeller protein-associated neurodegeneration to Neurodegeneration with brain iron accumulation 5, OMIM:300894
Dystonia, chorea or related movement disorder, adult onset v1.97 VPS35 Arina Puzriakova Phenotypes for gene: VPS35 were changed from PARK17; PARKINSON DISEASE 17; Parkinson disease 17, 614203; Parkinson Disease, Dominant; late onset parkinson disease to Parkinson disease 17, OMIM:614203
Dystonia, chorea or related movement disorder, adult onset v1.96 VPS13A Arina Puzriakova Phenotypes for gene: VPS13A were changed from complex parkinsonism; Choreoacanthocytosis 200150 to Choreoacanthocytosis, OMIM:200150
Dystonia, chorea or related movement disorder, adult onset v1.95 TUBB4A Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with Leukodystrophy, hypomyelinating, 6, OMIM:612438
Dystonia, chorea or related movement disorder, adult onset v1.95 TUBB4A Arina Puzriakova Phenotypes for gene: TUBB4A were changed from Complex parkinsonism; hypomyelinating leukodystrophy 6; ?Dystonia 4, torsion, autosomal dominant, 128101; Dystonia; hereditary whispering dysphonia to Dystonia 4, torsion, autosomal dominant, OMIM:128101
Dystonia, chorea or related movement disorder, adult onset v1.94 TIMM8A Arina Puzriakova Publications for gene: TIMM8A were set to 22736418
Dystonia, chorea or related movement disorder, adult onset v1.93 TIMM8A Arina Puzriakova Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, 304700; Deafness-Dystonia-Optic Neuronopathy Syndrome to Mohr-Tranebjaerg syndrome, OMIM:304700
Dystonia, chorea or related movement disorder, adult onset v1.92 THAP1 Arina Puzriakova Phenotypes for gene: THAP1 were changed from Dystonia 6, torsion, 602629; Dystonia to Dystonia 6, torsion, OMIM:602629
Dystonia, chorea or related movement disorder, adult onset v1.91 TBK1 Arina Puzriakova Phenotypes for gene: TBK1 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 4, 616439 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 4, OMIM:616439
Dystonia, chorea or related movement disorder, adult onset v1.90 SYNJ1 Arina Puzriakova Phenotypes for gene: SYNJ1 were changed from juvenile Parkinsonism; Early Onset Complex Disease; Parkinson disease 20, early-onset, 615530; Parkinson disease 20, early-onset to Parkinson disease 20, early-onset, OMIM:615530
Dystonia, chorea or related movement disorder, adult onset v1.89 SPR Arina Puzriakova Publications for gene: SPR were set to http://www.ncbi.nlm.nih.gov/books/NBK1155/; 22522443
Dystonia, chorea or related movement disorder, adult onset v1.88 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716; Dopa-Responsive Dystonia; paediatric form of dopa responsive dystonia; Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Dystonia, chorea or related movement disorder, adult onset v1.87 SPG11 Arina Puzriakova Phenotypes for gene: SPG11 were changed from Complex parkinsonism; hereditary spastic paraparesis; Early Onset Complex Disease; early onset parkinsonism, levo dopa responsve to Spastic paraplegia 11, autosomal recessive, OMIM:604360; Charcot-Marie-Tooth disease, axonal, type 2X, OMIM:616668; Amyotrophic lateral sclerosis 5, juvenile, OMIM:602099
Hypogonadotropic hypogonadism (GMS) v1.40 IL17RD Ivone Leong reviewed gene: IL17RD: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism (GMS) v1.40 IL17RD Ivone Leong Tag Q2_21_MOI tag was added to gene: IL17RD.
Hypogonadotropic hypogonadism (GMS) v1.40 IL17RD Ivone Leong Phenotypes for gene: IL17RD were changed from Hypogonadotropic hypogonadism type 18 (OMIM 615267) to Hypogonadotropic hypogonadism 18 with or without anosmia, OMIM:615267
Dystonia, chorea or related movement disorder, adult onset v1.86 SNCA Arina Puzriakova Phenotypes for gene: SNCA were changed from Autosomal dominant Parkinson's disease with alpha-synuclein rearrangements (PARK1/4); Dementia, Lewy body, 127750; Parkinson disease 4, 605543; Parkinson disease 1, 168601 to Dementia, Lewy body, OMIM:127750; Parkinson disease 4, OMIM:605543; Parkinson disease 1, OMIM:168601
Hypogonadotropic hypogonadism (GMS) v1.39 IL17RD Ivone Leong Publications for gene: IL17RD were set to
Dystonia, chorea or related movement disorder, adult onset v1.85 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease; hypermanganesemia with dystonia-1 (HMNDYT1), increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, Brain MRI shows hyperintensities in the basal ganglia to Hypermanganesemia with dystonia 1, OMIM:613280
Dystonia, chorea or related movement disorder, adult onset v1.84 SLC2A1 Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 and {Epilepsy, idiopathic generalized, susceptibility to, 12}, OMIM:614847
Dystonia, chorea or related movement disorder, adult onset v1.84 SLC2A1 Arina Puzriakova Phenotypes for gene: SLC2A1 were changed from EPILEPSY, IDIOPATHIC GENERALIZED; dystonia 9; GLUT1 deficiency syndrome 2; GLUT1 deficiency syndrome 1; GLUT1 deficiency syndrome 2, childhood onset; Dystonia; GLUT1 deficiency syndrome 1, infantile onset, severe; GLUT1 DEFICIENCY SYNDROME 1; GLUT1 deficiency syndrome 1, 606777; paroxysmal exertion-induced dyskinesia with or without epilepsy and/or hemolytic anemia to Dystonia 9, OMIM:601042; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126
Dystonia, chorea or related movement disorder, adult onset v1.83 SLC20A2 Arina Puzriakova Phenotypes for gene: SLC20A2 were changed from Basal ganglia calcification, idiopathic, 1 213600 to Basal ganglia calcification, idiopathic, 1, OMIM:213600
Dystonia, chorea or related movement disorder, adult onset v1.82 SLC19A3 Arina Puzriakova Phenotypes for gene: SLC19A3 were changed from Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2) 607483 to Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2), OMIM:607483
Dystonia, chorea or related movement disorder, adult onset v1.81 SGCE Arina Puzriakova Phenotypes for gene: SGCE were changed from Myoclonus dystonia syndrome; Myoclonus-Dystonia; maternally imprinted Dystonia-11, myoclonic, 159900 to Dystonia-11, myoclonic, OMIM:159900
Dystonia, chorea or related movement disorder, adult onset v1.80 RNF216 Arina Puzriakova Phenotypes for gene: RNF216 were changed from Cerebellar ataxia and hypogonadotropic hypogonadism, 212840 to Cerebellar ataxia and hypogonadotropic hypogonadism, OMIM:212840
Dystonia, chorea or related movement disorder, adult onset v1.79 RAB39B Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with Mental retardation, X-linked 72, OMIM:300271
Dystonia, chorea or related movement disorder, adult onset v1.79 RAB39B Arina Puzriakova Phenotypes for gene: RAB39B were changed from Waisman syndrome 311510; early-onset parkinsonism and intellectual disability to Waisman syndrome, OMIM:311510
Dystonia, chorea or related movement disorder, adult onset v1.78 PRRT2 Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with Seizures, benign familial infantile, 2, OMIM:605751
Dystonia, chorea or related movement disorder, adult onset v1.78 PRRT2 Arina Puzriakova Phenotypes for gene: PRRT2 were changed from SEIZURES, BENIGN FAMILIAL INFANTILE, 2; episodic kinesigenic dyskinesia; EPISODIC KINESIGENIC DYSKINESIA 1; dystonia and occasionally hemiplegic migraine and epilepsy; CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS to Episodic kinesigenic dyskinesia 1, OMIM:128200; Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066
Dystonia, chorea or related movement disorder, adult onset v1.77 PRNP Arina Puzriakova Added comment: Comment on phenotypes: This gene is also associated with {Kuru, susceptibility to}, OMIM:245300; Insomnia, fatal familial, OMIM:600072; Spongiform encephalopathy with neuropsychiatric features, OMIM:606688
Dystonia, chorea or related movement disorder, adult onset v1.77 PRNP Arina Puzriakova Phenotypes for gene: PRNP were changed from Cerebral amyloid angiopathy, PRNP-related 137440; Huntington disease-like 1 603218; Gerstmann-Straussler disease 137440; Creutzfeldt-Jakob disease 123400 to Cerebral amyloid angiopathy, PRNP-related, OMIM:137440; Huntington disease-like 1, OMIM:603218; Gerstmann-Straussler disease, OMIM:137440; Creutzfeldt-Jakob disease, OMIM:123400
Dystonia, chorea or related movement disorder, adult onset v1.76 PRKRA Arina Puzriakova Publications for gene: PRKRA were set to 24142417; 22842711; 26990861; 25142429; 18420150 - a novel heterozygous variant c.266_267delAT; PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previoulsy reported cases. The Authors state Screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance; p.H89fsX20 was reported in a proband with early childhood-onset leg dystonia (though testing in the parents was not mentioned).; 25737287; 25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous; 25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism; 18420150; 18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L); 22842711 describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa; http://www.ncbi.nlm.nih.gov/books/NBK1155/; 24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation; 18243799; 25914261
Dystonia, chorea or related movement disorder, adult onset v1.75 PRKRA Arina Puzriakova changed review comment from: - PMID: 18420150 - a novel heterozygous variant c.266_267delAT identified in a patient with generalised dystonia

- PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previously reported cases. The authors state screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance

- PMID: 25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous
25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism

- PMID: 18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L)

- PMID: 22842711 - describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa

- PMID: 24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation; to: Copied and removed from publications field:

- PMID: 18420150 - a novel heterozygous variant c.266_267delAT identified in a patient with generalised dystonia

- PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previously reported cases. The authors state screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance

- PMID: 25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous
25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism

- PMID: 18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L)

- PMID: 22842711 - describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa

- PMID: 24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation
Dystonia, chorea or related movement disorder, adult onset v1.75 PRKRA Arina Puzriakova commented on gene: PRKRA
Dystonia, chorea or related movement disorder, adult onset v1.75 PRKRA Arina Puzriakova Phenotypes for gene: PRKRA were changed from Early-Onset Generalized Dystonia-Parkinsonism; Early Onset Complex Disease; Dystonia 16; early-Onset Generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa; early-onset generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa; Dystonia; Dystonia 16, 612067 to Dystonia 16, OMIM:612067
Dystonia, chorea or related movement disorder, adult onset v1.74 PRKN Arina Puzriakova Publications for gene: PRKN were set to PMID: 22956510
Dystonia, chorea or related movement disorder, adult onset v1.73 PRKN Arina Puzriakova Phenotypes for gene: PRKN were changed from Parkinson Disease, Juvenile; juvenile parkinsonism/dystonia; Dystonia; Parkinson disease, juvenile, type 2; Parkinson Disease 2, Autosomal Recessive Juvenile to Parkinson disease, juvenile, type 2, OMIM:600116
Dystonia, chorea or related movement disorder, adult onset v1.72 PNKD Arina Puzriakova Phenotypes for gene: PNKD were changed from Familial Paroxysmal Nonkinesigenic Dyskinesia; PAROXYSMAL NONKINESIGENIC DYSKINESIA 1; Paroxysmal nonkinesigenic dyskinesia, 118800 to Paroxysmal nonkinesigenic dyskinesia 1, OMIM:118800
Dystonia, chorea or related movement disorder, adult onset v1.71 PLA2G6 Arina Puzriakova Publications for gene: PLA2G6 were set to 18799783; 18570303; 16783378
Neurodegenerative disorders, adult onset v2.174 PLA2G6 Arina Puzriakova Phenotypes for gene: PLA2G6 were changed from Infantile neuroaxonal dystrophy 1, OMIM:256600; Neurodegeneration with brain iron accumulation 2B, OMIM:610217; Parkinson disease 14, OMIM:612953 to Parkinson disease 14, autosomal recessive, OMIM:612953; Neurodegeneration with brain iron accumulation 2B, OMIM:610217
Dystonia, chorea or related movement disorder, adult onset v1.70 PLA2G6 Arina Puzriakova Phenotypes for gene: PLA2G6 were changed from PLA2G6-associated neurodegeneration; Parkinson disease 14, autosomal recessive 612953; Neurodegeneration with brain iron accumulation 2B 610217; Infantile neuroaxonal dystrophy 1 256600 to Parkinson disease 14, autosomal recessive, OMIM:612953; Neurodegeneration with brain iron accumulation 2B, OMIM:610217
Dystonia, chorea or related movement disorder, adult onset v1.69 PINK1 Arina Puzriakova Publications for gene: PINK1 were set to
Dystonia, chorea or related movement disorder, adult onset v1.68 PINK1 Arina Puzriakova Phenotypes for gene: PINK1 were changed from Parkinson Disease 6, Autosomal Recessive Early-Onset; Parkinson disease 6, early onset, 605909; Dystonia to Parkinson disease 6, early onset, OMIM:605909
Dystonia, chorea or related movement disorder, adult onset v1.67 PDGFRB Arina Puzriakova Phenotypes for gene: PDGFRB were changed from Basal ganglia calcification, idiopathic, 4 615007 to Basal ganglia calcification, idiopathic, 4, OMIM:615007
Hypogonadotropic hypogonadism (GMS) v1.38 DUSP6 Ivone Leong Phenotypes for gene: DUSP6 were changed from Hypogonadotropic hypogonadism 19 with or without anosmia, MIM# 615269 to Hypogonadotropic hypogonadism 19 with or without anosmia, OMIM:615269
Hypogonadotropic hypogonadism (GMS) v1.37 LEPR Ivone Leong Tag Q2_21_rating tag was added to gene: LEPR.
Hypogonadotropic hypogonadism (GMS) v1.37 LEPR Ivone Leong Classified gene: LEPR as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.37 LEPR Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hypogonadotropic hypogonadism (GMS) v1.37 LEPR Ivone Leong Gene: lepr has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.36 LEPR Ivone Leong Phenotypes for gene: LEPR were changed from Obesity, morbid, due to leptin receptor deficiency (MIM#614963) to Obesity, morbid, due to leptin receptor deficiency, OMIM:614963
Hypogonadotropic hypogonadism (GMS) v1.35 LEP Ivone Leong Classified gene: LEP as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.35 LEP Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hypogonadotropic hypogonadism (GMS) v1.35 LEP Ivone Leong Gene: lep has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.34 LEP Ivone Leong Tag Q2_21_rating tag was added to gene: LEP.
Dystonia, chorea or related movement disorder, adult onset v1.66 PDGFB Arina Puzriakova Publications for gene: PDGFB were set to 26129893
Dystonia, chorea or related movement disorder, adult onset v1.65 PDGFB Arina Puzriakova Phenotypes for gene: PDGFB were changed from Basal ganglia calcification, idiopathic, 5 615483 to Basal ganglia calcification, idiopathic, 5, OMIM:615483
Dystonia, chorea or related movement disorder, adult onset v1.64 PDE10A Arina Puzriakova Publications for gene: PDE10A were set to 27058446; 27058447; 28949041; 29130591; 30345538
Hypogonadotropic hypogonadism (GMS) v1.34 LEP Ivone Leong Phenotypes for gene: LEP were changed from Obesity, morbid, due to leptin deficiency (MIM#614962) to Obesity, morbid, due to leptin deficiency, OMIM:614962
Dystonia, chorea or related movement disorder, adult onset v1.63 PDE10A Arina Puzriakova Publications for gene: PDE10A were set to 27058447; 27058446
Hypogonadotropic hypogonadism (GMS) v1.33 GNRH1 Ivone Leong commented on gene: GNRH1
Hypogonadotropic hypogonadism (GMS) v1.33 GNRH1 Ivone Leong Tag Q2_21_rating tag was added to gene: GNRH1.
Dystonia, chorea or related movement disorder, adult onset v1.62 PDE10A Arina Puzriakova Phenotypes for gene: PDE10A were changed from Striatal degeneration, autosomal dominant 616922; Dyskinesia, limb and orofacial, infantile-onset 616921 to Striatal degeneration, autosomal dominant, OMIM:616922; Dyskinesia, limb and orofacial, infantile-onset, OMIM:616921
Dystonia, chorea or related movement disorder, adult onset v1.61 PDE10A Arina Puzriakova Tag Q2_21_rating tag was added to gene: PDE10A.
Dystonia, chorea or related movement disorder, adult onset v1.61 PDE10A Arina Puzriakova commented on gene: PDE10A
Hypogonadotropic hypogonadism (GMS) v1.33 GNRH1 Ivone Leong Phenotypes for gene: GNRH1 were changed from Hypogonadotropic hypogonadism 12 with or without anosmia, OMIM:614841 to ?Hypogonadotropic hypogonadism 12 with or without anosmia, OMIM:614841
Hypogonadotropic hypogonadism (GMS) v1.32 GNRH1 Ivone Leong Phenotypes for gene: GNRH1 were changed from Hypogonadotropic hypogonadism type 12 (OMIM 614841) to Hypogonadotropic hypogonadism 12 with or without anosmia, OMIM:614841
Hypogonadotropic hypogonadism (GMS) v1.31 GNRH1 Ivone Leong Publications for gene: GNRH1 were set to
Neurodegenerative disorders, adult onset v2.173 VPS13C Ivone Leong Phenotypes for gene: VPS13C were changed from Parkinson disease 23, autosomal recessive, early onset; 616840 to Parkinson disease 23, autosomal recessive, early onset, OMIM:616840
Neurodegenerative disorders, adult onset v2.172 TUBB4A Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Leukodystrophy, hypomyelinating, 6 612438;?Dystonia 4, torsion, autosomal dominant, 128101;hypomyelinating leukodystrophy 6;Implicated autosomal dominant variants in two families with ataxia;Dystonia;Torsion dystonia 4 (128101) - some individuals with ataxia;ataxia;hereditary whispering dysphonia;Complex parkinsonism;hypomyelinating leukodystrophy 6 (612438) - ataxia reported.;Dystonia 4, torsion, autosomal dominant 128101
Neurodegenerative disorders, adult onset v2.172 TUBB4A Ivone Leong Phenotypes for gene: TUBB4A were changed from Leukodystrophy, hypomyelinating, 6 612438; ?Dystonia 4, torsion, autosomal dominant, 128101; hypomyelinating leukodystrophy 6; Implicated autosomal dominant variants in two families with ataxia; Dystonia; Torsion dystonia 4 (128101) - some individuals with ataxia; ataxia; hereditary whispering dysphonia; Complex parkinsonism; hypomyelinating leukodystrophy 6 (612438) - ataxia reported.; Dystonia 4, torsion, autosomal dominant 128101 to Leukodystrophy, hypomyelinating, 6, OMIM:612438; Dystonia 4, torsion, autosomal dominant, OMIM:128101
Neurodegenerative disorders, adult onset v2.171 TUBA4A Ivone Leong Phenotypes for gene: TUBA4A were changed from Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, 616208 to Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, OMIM:616208
Neurodegenerative disorders, adult onset v2.170 TAF1 Ivone Leong Phenotypes for gene: TAF1 were changed from Dystonia-Parkinsonism, X-linked, 314250 to Dystonia-Parkinsonism, X-linked, OMIM:314250
Neurodegenerative disorders, adult onset v2.169 TAF1 Ivone Leong Phenotypes for gene: TAF1 were changed from SVA retrotransposon insertion Dystonia-Parkinsonism, X-linked, 314250; (NB complex mutation); Dystonia-Parkinsonism, X-linked, 314250 to Dystonia-Parkinsonism, X-linked, 314250
Neurodegenerative disorders, adult onset v2.168 SS18L1 Ivone Leong Phenotypes for gene: SS18L1 were changed from Amyotrophic lateral sclerosis 105400 to Amyotrophic lateral sclerosis, MONDO:0004976
Neurodegenerative disorders, adult onset v2.167 SS18L1 Ivone Leong Publications for gene: SS18L1 were set to 23708140; 24360741
Neurodegenerative disorders, adult onset v2.166 SNCB Ivone Leong Phenotypes for gene: SNCB were changed from Dementia, Lewy body, 127750 to Dementia, Lewy body, OMIM:127750
Neurodegenerative disorders, adult onset v2.165 SLC30A10 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
hypermanganesemia with dystonia-1 (HMNDYT1), increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, Brain MRI shows hyperintensities in the basal ganglia;Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, andChronic Liver Disease;Hypermanganesemia with dystonia, polycythemia, and cirrhosis, 613280;Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease
Neurodegenerative disorders, adult onset v2.165 SLC30A10 Ivone Leong Phenotypes for gene: SLC30A10 were changed from hypermanganesemia with dystonia-1 (HMNDYT1), increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, Brain MRI shows hyperintensities in the basal ganglia; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, andChronic Liver Disease; Hypermanganesemia with dystonia, polycythemia, and cirrhosis, 613280; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease to Hypermanganesemia with dystonia 1, OMIM:613280
Dystonia, chorea or related movement disorder, adult onset v1.61 PDE10A Arina Puzriakova Tag Q2_21_MOI tag was added to gene: PDE10A.
Neurodegenerative disorders, adult onset v2.164 SIGMAR1 Ivone Leong Phenotypes for gene: SIGMAR1 were changed from Amyotrophic lateral sclerosis 16, juvenile, 614373 to ?Amyotrophic lateral sclerosis 16, juvenile, OMIM:614373
Neurodegenerative disorders, adult onset v2.163 PRPH Ivone Leong Phenotypes for gene: PRPH were changed from 170710; Amyotrophic lateral sclerosis, susceptibility to to {Amyotrophic lateral sclerosis, susceptibility to}, OMIM:170710
Neurodegenerative disorders, adult onset v2.162 PRKRA Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
early-onset generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa;Early-Onset Generalized Dystonia-Parkinsonism;Dystonia 16;Dystonia;Dystonia 16, 612067;early-Onset Generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa;Early Onset Complex Disease
Neurodegenerative disorders, adult onset v2.162 PRKRA Ivone Leong Phenotypes for gene: PRKRA were changed from early-onset generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa; Early-Onset Generalized Dystonia-Parkinsonism; Dystonia 16; Dystonia; Dystonia 16, 612067; early-Onset Generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa; Early Onset Complex Disease to Dystonia 16, OMIM:612067
Neurodegenerative disorders, adult onset v2.161 NEK1 Ivone Leong Phenotypes for gene: NEK1 were changed from Amyotrophic lateral sclerosis, susceptibility to, 24; 617892 to {Amyotrophic lateral sclerosis, susceptibility to, 24}, OMIM:617892
Neurodegenerative disorders, adult onset v2.160 MATR3 Ivone Leong Phenotypes for gene: MATR3 were changed from Amyotrophic lateral sclerosis 21 to Amyotrophic lateral sclerosis 21, OMIM:606070
Dystonia, chorea or related movement disorder, adult onset v1.61 PARK7 Arina Puzriakova Phenotypes for gene: PARK7 were changed from 606324; Parkinson disease 7 autosomal recessive early-onset to Parkinson disease 7, autosomal recessive early-onset, OMIM:606324
Neurodegenerative disorders, adult onset v2.159 MARS2 Ivone Leong Phenotypes for gene: MARS2 were changed from Spastic ataxia 3, autosomal recessive to Spastic ataxia 3, autosomal recessive, OMIM:611390
Dystonia, chorea or related movement disorder, adult onset v1.60 PANK2 Arina Puzriakova Phenotypes for gene: PANK2 were changed from pantothenate kinase-associated neurodegeneration; Neurodegeneration with brain iron accumulation 1; Early Onset Complex Disease; Dystonia; 234200 to Neurodegeneration with brain iron accumulation 1, OMIM:234200
Neurodegenerative disorders, adult onset v2.158 HNRNPA2B1 Ivone Leong Phenotypes for gene: HNRNPA2B1 were changed from Amyotrophic lateral sclerosis to Amyotrophic lateral sclerosis, MONDO:0004976; ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422
Neurodegenerative disorders, adult onset v2.157 GIGYF2 Ivone Leong Phenotypes for gene: GIGYF2 were changed from {Parkinson disease 11}; Susceptibility to Parkinson disease 11, 607688 to {Parkinson disease 11}, OMIM:607688
Neurodegenerative disorders, adult onset v2.156 GCDH Ivone Leong Phenotypes for gene: GCDH were changed from Dystonia; Glutaricaciduria, type I, 231670 to Dystonia; Glutaricaciduria, type I, OMIM:231670
Dystonia, chorea or related movement disorder, adult onset v1.59 NKX2-1 Arina Puzriakova Phenotypes for gene: NKX2-1 were changed from Choreoathetosis, hypothyroidism, and neonatal respiratory distress; Chorea, hereditary benign 118700 to Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978; Chorea, hereditary benign, OMIM:118700
Neurodegenerative disorders, adult onset v2.155 GBA Ivone Leong Phenotypes for gene: GBA were changed from {Parkinson disease, late-onset, susceptibility to}, 168600; Gaucher disease, type I, 230800 to {Parkinson disease, late-onset, susceptibility to}, OMIM:168600; Gaucher disease, type I, OMIM:230800
Neurodegenerative disorders, adult onset v2.154 EWSR1 Ivone Leong Phenotypes for gene: EWSR1 were changed from Amyotrophic lateral sclerosis to Amyotrophic lateral sclerosis, MONDO:0004976
Neurodegenerative disorders, adult onset v2.153 EIF4G1 Ivone Leong Phenotypes for gene: EIF4G1 were changed from Parkinsons disease 18, 614251 to {Parkinsons disease 18}, OMIM:614251
Neurodegenerative disorders, adult onset v2.152 DAO Ivone Leong Phenotypes for gene: DAO were changed from Amyotrophic lateral sclerosis to Amyotrophic lateral sclerosis, MONDO:0004976
Neurodegenerative disorders, adult onset v2.151 COQ2 Ivone Leong Phenotypes for gene: COQ2 were changed from Multiple system atrophy, susceptibility to, 146500 to {Multiple system atrophy, susceptibility to}, OMIM:146500
Neurodegenerative disorders, adult onset v2.150 CIZ1 Ivone Leong Phenotypes for gene: CIZ1 were changed from Dystonia 23, 614860 to Dystonia 23, MONDO:0013928
Neurodegenerative disorders, adult onset v2.149 CIZ1 Ivone Leong Publications for gene: CIZ1 were set to
Neurodegenerative disorders, adult onset v2.148 CCDC88C Ivone Leong Phenotypes for gene: CCDC88C were changed from autosomal dominant spinocerebellar ataxia to ?Spinocerebellar ataxia 40, OMIM:616053
Neurodegenerative disorders, adult onset v2.147 ATP6AP2 Ivone Leong Phenotypes for gene: ATP6AP2 were changed from ?Parkinsonism with spasticity, X-linked 300911; Mental retardation, X-linked, syndromic, Hedera type 300423 to ?Parkinsonism with spasticity, X-linked, OMIM:300911; Mental retardation, X-linked, syndromic, Hedera type, OMIM:300423
Neurodegenerative disorders, adult onset v2.146 ATP2B3 Ivone Leong Phenotypes for gene: ATP2B3 were changed from Spinocerebellar ataxia, X-linked 1 to ?Spinocerebellar ataxia, X-linked 1, OMIM:302500
Neurodegenerative disorders, adult onset v2.145 ARHGEF28 Ivone Leong Phenotypes for gene: ARHGEF28 were changed from Amyotrophic lateral sclerosis to Amyotrophic lateral sclerosis, MONDO:0004976
Neurodegenerative disorders, adult onset v2.144 AP5Z1 Ivone Leong Phenotypes for gene: AP5Z1 were changed from Spastic Paraplegia, Recessive; Spastic paraplegia 48, autosomal recessive to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Neurodegenerative disorders, adult onset v2.143 XPR1 Ivone Leong Phenotypes for gene: XPR1 were changed from to Basal ganglia calcification, idiopathic, 6, OMIM:605237
Neurodegenerative disorders, adult onset v2.142 WDR45 Ivone Leong Phenotypes for gene: WDR45 were changed from Dystonia; beta-propeller protein-associated neurodegeneration to Dystonia; Neurodegeneration with brain iron accumulation 5, OMIM:300894
Neurodegenerative disorders, adult onset v2.141 VPS35 Ivone Leong Phenotypes for gene: VPS35 were changed from Parkinson disease 17, 614203; Parkinson Disease, Dominant; late onset parkinson disease; PARKINSON DISEASE 17; PARK17 to {Parkinson disease 17}, OMIM:614203
Neurodegenerative disorders, adult onset v2.140 VPS13A Ivone Leong Phenotypes for gene: VPS13A were changed from Choreoacanthocytosis, OMIM:200150 to Choreoacanthocytosis, OMIM:200150
Neurodegenerative disorders, adult onset v2.139 VPS13A Ivone Leong Phenotypes for gene: VPS13A were changed from complex parkinsonism; Complex parkinsonism; 200150; Choreoacanthocytosis to Choreoacanthocytosis, OMIM:200150
Neurodegenerative disorders, adult onset v2.138 VCP Ivone Leong Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954; familial amyotrophic lateral sclerosis (ALS14); Amyotrophic Lateral Sclerosis, Dominant to Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, OMIM:613954
Neurodegenerative disorders, adult onset v2.137 VAPB Ivone Leong Phenotypes for gene: VAPB were changed from Amyotrophic lateral sclerosis 8, 608627; Amyotrophic Lateral Sclerosis, Dominant to Amyotrophic lateral sclerosis 8, OMIM:608627
Neurodegenerative disorders, adult onset v2.136 UBQLN2 Ivone Leong Phenotypes for gene: UBQLN2 were changed from Amyotrophic Lateral Sclerosis, Dominant; Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia, 300857 to Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia, OMIM:300857
Neurodegenerative disorders, adult onset v2.135 TYROBP Ivone Leong Phenotypes for gene: TYROBP were changed from Dementia to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1, OMIM:221770
Neurodegenerative disorders, adult onset v2.134 TTC19 Ivone Leong Phenotypes for gene: TTC19 were changed from Mitochondrial complex III deficiency, nuclear type 2, 615157 to Mitochondrial complex III deficiency, nuclear type 2, OMIM:615157
Neurodegenerative disorders, adult onset v2.133 TREM2 Ivone Leong Phenotypes for gene: TREM2 were changed from Dementia; Dystonia to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, OMIM:618193; Dystonia
Neurodegenerative disorders, adult onset v2.132 TMEM240 Ivone Leong Phenotypes for gene: TMEM240 were changed from Spinocerebellar ataxia 21, 607454 to Spinocerebellar ataxia 21, OMIM:607454
Neurodegenerative disorders, adult onset v2.131 TBK1 Ivone Leong Phenotypes for gene: TBK1 were changed from FTLD; ALS; fronto-temporal dementia; Amyotrophic lateral sclerosis to Frontotemporal dementia and/or amyotrophic lateral sclerosis 4, OMIM:616439
Neurodegenerative disorders, adult onset v2.130 TARDBP Ivone Leong Phenotypes for gene: TARDBP were changed from Amyotrophic Lateral Sclerosis, Dominant; Frontotemporal Dementia; Amyotrophic lateral sclerosis 10, with or without FTD, 612069 to Amyotrophic lateral sclerosis 10, with or without FTD, OMIM:612069
Neurodegenerative disorders, adult onset v2.129 SYNJ1 Ivone Leong Phenotypes for gene: SYNJ1 were changed from Parkinson disease 20, early-onset, 615530; Early Onset Complex Disease; juvenile Parkinsonism; Parkinson disease 20, early-onset to Parkinson disease 20, early-onset, OMIM:615530
Neurodegenerative disorders, adult onset v2.128 SQSTM1 Ivone Leong Phenotypes for gene: SQSTM1 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 3, OMIM:616437
Neurodegenerative disorders, adult onset v2.127 SPG11 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
early onset parkinsonism, levo dopa responsve;Spastic paraplegia 11, autosomal recessive;Complex parkinsonism;hereditary spastic paraparesis;Early Onset Complex Disease
Neurodegenerative disorders, adult onset v2.127 SPG11 Ivone Leong Phenotypes for gene: SPG11 were changed from early onset parkinsonism, levo dopa responsve; Spastic paraplegia 11, autosomal recessive; Complex parkinsonism; hereditary spastic paraparesis; Early Onset Complex Disease to early onset parkinsonism, levo dopa responsve; Spastic paraplegia 11, autosomal recessive, OMIM:604360; Complex parkinsonism; hereditary spastic paraparesis; Amyotrophic lateral sclerosis 5, juvenile, OMIM:602099
Neurodegenerative disorders, adult onset v2.126 SPAST Ivone Leong Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant to Spastic paraplegia 4, autosomal dominant, OMIM:182601
Neurodegenerative disorders, adult onset v2.125 SOD1 Ivone Leong Phenotypes for gene: SOD1 were changed from Amyotrophic lateral sclerosis 1, 105400; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis, Dominant to Amyotrophic lateral sclerosis 1, OMIM:105400
Neurodegenerative disorders, adult onset v2.124 SNCA Ivone Leong Phenotypes for gene: SNCA were changed from Autosomal dominant Parkinson's disease with alpha-synuclein rearrangements (PARK1/4); Parkinson disease 4, 605543; Parkinson disease 1, 168601; Dementia, Lewy body, 127750 to Parkinson disease 4, OMIM:605543; Parkinson disease 1, OMIM:168601; Dementia, Lewy body, OMIM:127750
Neurodegenerative disorders, adult onset v2.123 SLC20A2 Ivone Leong Phenotypes for gene: SLC20A2 were changed from Dystonia; Basal ganglia calcification, idiopathic, 1, 158378 to Dystonia; Basal ganglia calcification, idiopathic, 1, OMIM:158378
Neurodegenerative disorders, adult onset v2.122 SETX Ivone Leong Phenotypes for gene: SETX were changed from Amyotrophic lateral sclerosis 4, juvenile 602433; ataxia with oculomotor apraxia type 2 (AOA2), juvenile amyotrophic lateral sclerosis (ALS4) and autosomal dominant ataxia; Ataxia-ocular apraxia-2 to Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Neurodegenerative disorders, adult onset v2.121 RNF216 Ivone Leong Phenotypes for gene: RNF216 were changed from Cerebellar ataxia and hypogonadotropic hypogonadism, 212840 to Cerebellar ataxia and hypogonadotropic hypogonadism, OMIM:212840
Neurodegenerative disorders, adult onset v2.120 PSEN2 Ivone Leong Phenotypes for gene: PSEN2 were changed from Dementia to Alzheimer disease-4, OMIM:606889
Neurodegenerative disorders, adult onset v2.119 PSEN1 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Acne inversa, familial, 3, 613737;Alzheimer disease, type 3, with spastic paraparesis and unusual plaques, 607822;Alzheimer disease, type 3, with spastic paraparesis and apraxia, 607822;Alzheimer disease, type 3, with spastic paraparesis and unusual plaques;Dystonia;Dementia, frontotemporal, 600274;Pick disease, 172700;Clinical syndrome Alzheimer disease;Alzheimer disease, type 3, 607822;Cardiomyopathy, dilated, 1U, 613694;Alzheimer disease, type 3, with spastic paraparesis and apraxia
Neurodegenerative disorders, adult onset v2.119 PSEN1 Ivone Leong Phenotypes for gene: PSEN1 were changed from Acne inversa, familial, 3, 613737; Alzheimer disease, type 3, with spastic paraparesis and unusual plaques, 607822; Alzheimer disease, type 3, with spastic paraparesis and apraxia, 607822; Alzheimer disease, type 3, with spastic paraparesis and unusual plaques; Dystonia; Dementia, frontotemporal, 600274; Pick disease, 172700; Clinical syndrome Alzheimer disease; Alzheimer disease, type 3, 607822; Cardiomyopathy, dilated, 1U, 613694; Alzheimer disease, type 3, with spastic paraparesis and apraxia to Alzheimer disease, type 3, with spastic paraparesis and unusual plaques, OMIM:607822; Alzheimer disease, type 3, with spastic paraparesis and apraxia, OMIM:607822; Dystonia; Dementia, frontotemporal, OMIM:600274; Pick disease, OMIM:172700; Alzheimer disease, type 3, OMIM:607822
Neurodegenerative disorders, adult onset v2.118 PRNP Ivone Leong Phenotypes for gene: PRNP were changed from Creutzfeldt-Jakob disease; Autosomal Dominant Ataxia; Insomnia, fatal familial; Huntington disease-like 1; Clinical syndrome Prion disease; Dementia; Gerstmann-Straussler disease to Creutzfeldt-Jakob disease, OMIM:123400; Huntington disease-like 1, OMIM:603218; Dementia; Gerstmann-Straussler disease, OMIM:137440
Neurodegenerative disorders, adult onset v2.117 PRKN Ivone Leong Phenotypes for gene: PRKN were changed from Parkinson disease, juvenile, type 2; Dystonia; Parkinson Disease 2, Autosomal Recessive Juvenile; juvenile parkinsonism/dystonia; Parkinson Disease, Juvenile to Parkinson disease, juvenile, type 2, OMIM:600116; Dystonia
Neurodegenerative disorders, adult onset v2.116 PLA2G6 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Infantile neuroaxonal dystrophy 1, 256600;PLA2G6-associated neurodegeneration;Neurodegeneration with brain iron accumulation 2B, 610217;Infantile neuroaxonal dystrophy 1 (#256600);Neurodegeneration with brain iron accumulation 2B (#610217);Parkinson disease 14 (#612953);Parkinson disease 14, 612953;Early Onset Complex Disease
Neurodegenerative disorders, adult onset v2.116 PLA2G6 Ivone Leong Phenotypes for gene: PLA2G6 were changed from Infantile neuroaxonal dystrophy 1, 256600; PLA2G6-associated neurodegeneration; Neurodegeneration with brain iron accumulation 2B, 610217; Infantile neuroaxonal dystrophy 1 (#256600); Neurodegeneration with brain iron accumulation 2B (#610217); Parkinson disease 14 (#612953); Parkinson disease 14, 612953; Early Onset Complex Disease to Infantile neuroaxonal dystrophy 1, OMIM:256600; Neurodegeneration with brain iron accumulation 2B, OMIM:610217; Parkinson disease 14, OMIM:612953
Neurodegenerative disorders, adult onset v2.115 PINK1 Ivone Leong Phenotypes for gene: PINK1 were changed from Parkinson disease 6, early onset, 605909; Dystonia; Parkinson Disease 6, Autosomal Recessive Early-Onset to Parkinson disease 6, early onset, OMIM:605909; Dystonia
Neurodegenerative disorders, adult onset v2.114 PFN1 Ivone Leong Phenotypes for gene: PFN1 were changed from Amyotrophic lateral sclerosis 18, 614808 to Amyotrophic lateral sclerosis 18, OMIM:614808
Dystonia, chorea or related movement disorder, adult onset v1.58 MAPT Arina Puzriakova Phenotypes for gene: MAPT were changed from Supranuclear palsy, progressive, 601104; clinical presentation suggestive of cortico-basal/PSP syndrome; Supranuclear palsy, progressive atypical, 260540; {Parkinson disease, susceptibility to}, 168600; Pick disease, 172700; Tauopathy and r; Dementia, frontotemporal, with or without parkinsonism, 600274; PARKINSON-DEMENTIA SYNDROME to Supranuclear palsy, progressive, OMIM:601104; Supranuclear palsy, progressive atypical, OMIM:260540; {Parkinson disease, susceptibility to}, OMIM:168600; Dementia, frontotemporal, with or without parkinsonism, OMIM:600274; Pick disease, OMIM:172700
Neurodegenerative disorders, adult onset v2.113 PDGFRB Ivone Leong Phenotypes for gene: PDGFRB were changed from Dystonia; Basal ganglia calcification, idiopathic, 4, 615007 to Dystonia; Basal ganglia calcification, idiopathic, 4, OMIM:615007
Neurodegenerative disorders, adult onset v2.112 PDGFB Ivone Leong Phenotypes for gene: PDGFB were changed from to Basal ganglia calcification, idiopathic, 5, OMIM:615483
Neurodegenerative disorders, adult onset v2.111 PARK7 Ivone Leong Phenotypes for gene: PARK7 were changed from Parkinson disease 7 autosomal recessive early-onset; 606324; Parkinson disease 7, autosomal recessive early-onset to Parkinson disease 7, autosomal recessive early-onset, OMIM:606324
Neurodegenerative disorders, adult onset v2.110 PANK2 Ivone Leong Phenotypes for gene: PANK2 were changed from Dystonia; Neurodegeneration with brain iron accumulation 1; 234200; Early Onset Complex Disease; pantothenate kinase-associated neurodegeneration to Dystonia; Neurodegeneration with brain iron accumulation 1, OMIM:234200
Neurodegenerative disorders, adult onset v2.109 OPTN Ivone Leong Phenotypes for gene: OPTN were changed from Glaucoma 1, open angle, E, 137760; Amyotrophic Lateral Sclerosis, Recessive to Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia, OMIM:613435
Neurodegenerative disorders, adult onset v2.108 NPC2 Ivone Leong Phenotypes for gene: NPC2 were changed from Dystonia; Niemann-Pick disease type C2 (#607625) to Dystonia; Niemann-Pick disease, type C2, OMIM:607625
Neurodegenerative disorders, adult onset v2.107 NPC1 Ivone Leong Phenotypes for gene: NPC1 were changed from Niemann-Pick disease types C1 and D (#257220) to Niemann-Pick disease, type C1, OMIM:257220; Niemann-Pick disease, type D, OMIM:257220
Dystonia, chorea or related movement disorder, adult onset v1.57 LYST Arina Puzriakova Phenotypes for gene: LYST were changed from albinism; peripheral neuropathy; Chediak-Higashi syndrome 214500; Parkinsonism to Chediak-Higashi syndrome, OMIM:214500
Neurodegenerative disorders, adult onset v2.106 NOTCH3 Ivone Leong Phenotypes for gene: NOTCH3 were changed from Dementia to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Neurodegenerative disorders, adult onset v2.105 NHLRC1 Ivone Leong Phenotypes for gene: NHLRC1 were changed from Epilepsy, progressive myoclonic 2B (Lafora) 254780 to Epilepsy, progressive myoclonic 2B (Lafora), OMIM:254780
Neurodegenerative disorders, adult onset v2.104 MAPT Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Dementia, frontotemporal, with or without parkinsonism, 600274;Supranuclear palsy, progressive, OMIM:601104;clinical presentation suggestive of cortico-basal/PSP syndrome;Parkinson disease, susceptibility to}, OMIM:168600;Pick disease, OMIM:172700;Clinical syndrome FTLD (Frontotemporal lobar degeneration);Supranuclear palsy, progressive atypical, OMIM:260540
Neurodegenerative disorders, adult onset v2.104 MAPT Ivone Leong Phenotypes for gene: MAPT were changed from Dementia, frontotemporal, with or without parkinsonism, 600274; Tauopathy and r; Supranuclear palsy, progressive, 601104; clinical presentation suggestive of cortico-basal/PSP syndrome; PARKINSON-DEMENTIA SYNDROME; {Parkinson disease, susceptibility to}, 168600; Pick disease, 172700; Clinical syndrome FTLD (Frontotemporal lobar degeneration); Supranuclear palsy, progressive atypical, 260540 to Dementia, frontotemporal, with or without parkinsonism, OMIM:600274; Tauopathy and r; Supranuclear palsy, progressive, 601104; clinical presentation suggestive of cortico-basal/PSP syndrome; PARKINSON-DEMENTIA SYNDROME; {Parkinson disease, susceptibility to}, 168600; Pick disease, 172700; Clinical syndrome FTLD (Frontotemporal lobar degeneration); Supranuclear palsy, progressive atypical, 260540
Dystonia, chorea or related movement disorder, adult onset v1.56 LRRK2 Arina Puzriakova Phenotypes for gene: LRRK2 were changed from LRRK2 G2019S mutation; Parkinson Disease, Dominant; Parkinson disease 8, 607060; PARKINSON DISEASE 8, AUTOSOMAL DOMINANT; Autosomal dominant Parkinson's disease; Parkinson Disease 8, Autosomal Dominant to {Parkinson disease 8}, OMIM:607060
Dystonia, chorea or related movement disorder, adult onset v1.55 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from Dystonia 28, childhood-onset 617284; early-onset dystonia to Dystonia 28, childhood-onset, OMIM:617284
Neurodegenerative disorders, adult onset v2.103 LYST Ivone Leong Phenotypes for gene: LYST were changed from Chediak-Higashi syndrome, OMIM:214500; peripheral neuropathy; Parkinsonism; albinism; spastic paraplegia to Chediak-Higashi syndrome, OMIM:214500; peripheral neuropathy; Parkinsonism; spastic paraplegia
Neurodegenerative disorders, adult onset v2.102 LYST Ivone Leong Phenotypes for gene: LYST were changed from Chediak-Higashi syndrome 214500; peripheral neuropathy; Parkinsonism; albinism; spastic paraplegia to Chediak-Higashi syndrome, OMIM:214500; peripheral neuropathy; Parkinsonism; albinism; spastic paraplegia
Neurodegenerative disorders, adult onset v2.101 LRRK2 Ivone Leong Phenotypes for gene: LRRK2 were changed from Parkinson Disease 8, Autosomal Dominant; Autosomal dominant Parkinson's disease; Parkinson Disease, Dominant; PARKINSON DISEASE 8, AUTOSOMAL DOMINANT; LRRK2 G2019S mutation; Parkinson disease 8, 607060 to LRRK2 G2019S mutation; {Parkinson disease 8}, OMIM:607060
Neurodegenerative disorders, adult onset v2.100 KIF5A Ivone Leong Phenotypes for gene: KIF5A were changed from Spastic paraplegia 10, autosomal dominant to Spastic paraplegia 10, autosomal dominant, OMIM:604187
Neurodegenerative disorders, adult onset v2.99 KIAA1161 Ivone Leong Phenotypes for gene: KIAA1161 were changed from Autosomal Recessive Primary Familial Brain Calcification; Basal ganglia calcification, idiopathic, 7, autosomal recessive, 618317 to Basal ganglia calcification, idiopathic, 7, autosomal recessive, OMIM:618317
Dystonia, chorea or related movement disorder, adult onset v1.54 KIAA1161 Arina Puzriakova Phenotypes for gene: KIAA1161 were changed from Autosomal Recessive Primary Familial Brain Calcification; Basal ganglia calcification, idiopathic, 7, autosomal recessive; Abnormal movements; Dystonia to Basal ganglia calcification, idiopathic, 7, autosomal recessive, OMIM:618317
Dystonia, chorea or related movement disorder, adult onset v1.53 HPCA Arina Puzriakova Phenotypes for gene: HPCA were changed from Dystonia 2, torsion, autosomal recessive, 224500; generalized dystonia with additional neurological features; childhood-onset generalized dystonia; adolescence-onset segmental dystonia to Dystonia 2, torsion, autosomal recessive, OMIM:224500
Dystonia, chorea or related movement disorder, adult onset v1.52 GTPBP2 Arina Puzriakova Phenotypes for gene: GTPBP2 were changed from Jaberi-Elahi syndrome, 617988; Dystonia to Jaberi-Elahi syndrome, OMIM:617988
Neurodegenerative disorders, adult onset v2.98 KCND3 Ivone Leong Phenotypes for gene: KCND3 were changed from Spinocerebellarataxia19,607346 to Spinocerebellarataxia19, OMIM:607346
Neurodegenerative disorders, adult onset v2.97 KCNC3 Ivone Leong Phenotypes for gene: KCNC3 were changed from Spinocerebellar ataxia 13 to Spinocerebellar ataxia 13, OMIM:605259
Neurodegenerative disorders, adult onset v2.96 ITM2B Ivone Leong Phenotypes for gene: ITM2B were changed from Dementia, familial British, 176500 to Dementia, familial British, OMIM:176500
Neurodegenerative disorders, adult onset v2.95 ITM2B Ivone Leong Publications for gene: ITM2B were set to 29525180; 10391242
Neurodegenerative disorders, adult onset v2.94 HTRA1 Ivone Leong Phenotypes for gene: HTRA1 were changed from Dementia; CARASIL syndrome 600142; Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 616779 to dementia (disease), MONDO:0001627; CARASIL syndrome, OMIM:600142; Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2, OMIM:616779
Dystonia, chorea or related movement disorder, adult onset v1.51 GRN Arina Puzriakova Phenotypes for gene: GRN were changed from Complex parkinsonism; frontotemporal lobar degeneration with TDP43 inclusions; clinical presentation suggestive of cortico-basal/PSP syndrome to Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485
Neurodegenerative disorders, adult onset v2.93 HNRNPA1 Ivone Leong Phenotypes for gene: HNRNPA1 were changed from ?Inclusion body myopathy wtih early-onset Paget disease without frontotemporal to ?Inclusion body myopathy wtih early-onset Paget disease without frontotemporal dementia type 3, OMIM:615424, Amyotrophic lateral sclerosis 20, OMIM:615426
Neurodegenerative disorders, adult onset v2.92 HNRNPA1 Ivone Leong Publications for gene: HNRNPA1 were set to 23455423
Dystonia, chorea or related movement disorder, adult onset v1.50 GNAL Arina Puzriakova Phenotypes for gene: GNAL were changed from adult-onset cranio-cervical dystonia; Dystonia 25, 615073 to Dystonia 25, OMIM:615073
Dystonia, chorea or related movement disorder, adult onset v1.49 GFAP Arina Puzriakova Phenotypes for gene: GFAP were changed from Alexander disease 203450 to Alexander disease, OMIM:203450
Dystonia, chorea or related movement disorder, adult onset v1.48 GCH1 Arina Puzriakova Phenotypes for gene: GCH1 were changed from Hyperphenylalaninemia, BH4-deficient, B, 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Dopa-Responsive Dystonia (DRD) to Hyperphenylalaninemia, BH4-deficient, B, OMIM:233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, OMIM:128230
Neurodegenerative disorders, adult onset v2.91 HEXA Ivone Leong Phenotypes for gene: HEXA were changed from GM2-gangliosidosis, several forms, 272800; Tay-Sachs disease, 272800 to GM2-gangliosidosis, several forms, OMIM:272800; Tay-Sachs disease, OMIM:272800
Neurodegenerative disorders, adult onset v2.90 GRN Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
clinical presentation suggestive of cortico-basal/PSP syndrome;Complex parkinsonism;Frontotemporal Dementia;frontotemporal lobar degeneration with TDP43 inclusions;Clinical syndrome FTLD (Frontotemporal lobar degeneration)
Neurodegenerative disorders, adult onset v2.90 GRN Ivone Leong Phenotypes for gene: GRN were changed from clinical presentation suggestive of cortico-basal/PSP syndrome; Complex parkinsonism; Frontotemporal Dementia; frontotemporal lobar degeneration with TDP43 inclusions; Clinical syndrome FTLD (Frontotemporal lobar degeneration) to Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485; Aphasia, primary progressive, OMIM:607485
Neurodegenerative disorders, adult onset v2.89 GFAP Ivone Leong Phenotypes for gene: GFAP were changed from Autosomal Dominant Ataxia; Alexander disease to Autosomal Dominant Ataxia; Alexander disease, OMIM:203450
Neurodegenerative disorders, adult onset v2.88 GCH1 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Dopa-Responsive Dystonia (DRD);progressive spastic paraplegia;Dystonia;Hyperphenylalaninemia, BH4-deficient, B, 233910;Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230;Spastic paraplegia
Neurodegenerative disorders, adult onset v2.88 GCH1 Ivone Leong Phenotypes for gene: GCH1 were changed from Dopa-Responsive Dystonia (DRD); progressive spastic paraplegia; Dystonia; Hyperphenylalaninemia, BH4-deficient, B, 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Spastic paraplegia to Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, OMIM:128230; Hyperphenylalaninemia, BH4-deficient, B, OMIM:233910; Spastic paraplegia
Dystonia, chorea or related movement disorder, adult onset v1.47 GBA Arina Puzriakova Phenotypes for gene: GBA were changed from {Parkinson disease, late-onset, susceptibility to}, 168600 to {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Neurodegenerative disorders, adult onset v2.87 GCH1 Ivone Leong Publications for gene: GCH1 were set to 25497597; http://www.ncbi.nlm.nih.gov/books/NBK1155/; 24509643; 24993959; 21935284
Dystonia, chorea or related movement disorder, adult onset v1.46 FTL Arina Puzriakova Phenotypes for gene: FTL were changed from Neurodegeneration with brain iron accumulation 3 606159; movement disorder to Neurodegeneration with brain iron accumulation 3, OMIM:606159
Dystonia, chorea or related movement disorder, adult onset v1.45 FTL Arina Puzriakova Publications for gene: FTL were set to http://www.ncbi.nlm.nih.gov/pubmed/24209436; 24209436
Neurodegenerative disorders, adult onset v2.86 FUS Ivone Leong Phenotypes for gene: FUS were changed from Dementia; Amyotrophic lateral sclerosis 6, autosomal recessive, with or without frontotemporal; Amyotrophic Lateral Sclerosis, Dominant to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, OMIM:608030
Neurodegenerative disorders, adult onset v2.85 FTL Ivone Leong Phenotypes for gene: FTL were changed from Neurodegeneration with brain iron accumulation 3; movement disorder to Neurodegeneration with brain iron accumulation 3, OMIM:606159
Neurodegenerative disorders, adult onset v2.84 FTL Ivone Leong Publications for gene: FTL were set to 24209436; http://www.ncbi.nlm.nih.gov/pubmed/24209436
Neurodegenerative disorders, adult onset v2.83 FIG4 Ivone Leong Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J, 611228; Amyotrophic Lateral Sclerosis, Dominant to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Amyotrophic lateral sclerosis 11, OMIM:612577
Neurodegenerative disorders, adult onset v2.82 FBXO7 Ivone Leong Phenotypes for gene: FBXO7 were changed from Parkinson Disease, Recessive; Dystonia; juvenile parkinsonism; parkinsonian-pyramidal syndrome; Parkinson disease 15, autosomal recessive, 260300; Early Onset Complex Disease to Dystonia; Parkinson disease 15, autosomal recessive, OMIM:260300
Neurodegenerative disorders, adult onset v2.81 EPM2A Ivone Leong Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Epilepsy, progressive myoclonic 2A (Lafora), OMIM:254780
Neurodegenerative disorders, adult onset v2.80 ELOVL4 Ivone Leong Phenotypes for gene: ELOVL4 were changed from Spinocerebellar ataxia 34 133190 to Spinocerebellar ataxia 34, OMIM:133190
Neurodegenerative disorders, adult onset v2.79 EIF2B5 Ivone Leong Phenotypes for gene: EIF2B5 were changed from Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease to Leukoencephalopathy with vanishing white matter, OMIM:603896
Neurodegenerative disorders, adult onset v2.78 EIF2B4 Ivone Leong Phenotypes for gene: EIF2B4 were changed from Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease to Leukoencephalopathy with vanishing white matter, OMIM:603896
Neurodegenerative disorders, adult onset v2.77 EIF2B3 Ivone Leong Phenotypes for gene: EIF2B3 were changed from Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease to Leukoencephalopathy with vanishing white matter, OMIM:603896
Dystonia, chorea or related movement disorder, adult onset v1.44 FBXO7 Arina Puzriakova Phenotypes for gene: FBXO7 were changed from Parkinson disease 15, autosomal recessive, 260300; Parkinson Disease, Recessive; Early Onset Complex Disease; juvenile parkinsonism; Dystonia; parkinsonian-pyramidal syndrome to Parkinson disease 15, autosomal recessive, OMIM:260300
Neurodegenerative disorders, adult onset v2.76 EIF2B2 Ivone Leong Phenotypes for gene: EIF2B2 were changed from Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease; Leukoencephalopathy with vanishing white matter, 603896 to Leukoencephalopathy with vanishing white matter, OMIM:603896
Neurodegenerative disorders, adult onset v2.75 EIF2B1 Ivone Leong Phenotypes for gene: EIF2B1 were changed from Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease; Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter to Leukoencephalopathy with vanishing white matter, OMIM:603896
Neurodegenerative disorders, adult onset v2.74 DNMT1 Ivone Leong Phenotypes for gene: DNMT1 were changed from Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, OMIM; 604121 to Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, OMIM:604121
Neurodegenerative disorders, adult onset v2.73 DNMT1 Ivone Leong Phenotypes for gene: DNMT1 were changed from Dementia, Deafness, and Sensory Neuropathy; Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, to Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, OMIM; 604121
Dystonia, chorea or related movement disorder, adult onset v1.43 DNAJC6 Arina Puzriakova Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19a, juvenile-onset; Parkinson disease 19, juvenile-onset, 615528; Parkinson disease 19b, early-onset to Parkinson disease 19, juvenile-onset, OMIM:615528; Parkinson disease 19b, early-onset, OMIM:615528
Neurodegenerative disorders, adult onset v2.72 DNAJC6 Ivone Leong Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19b, early-onset; Parkinson disease 19, juvenile-onset, 615528; Parkinson disease 19a, juvenile-onset to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a, juvenile-onset, OMIM:615528
Neurodegenerative disorders, adult onset v2.71 DNAJC5 Ivone Leong Phenotypes for gene: DNAJC5 were changed from Ceroid lipofuscinosis, neuronal, 4, Parry type 162350 to Ceroid lipofuscinosis, neuronal, 4, Parry type, OMIM:162350
Neurodegenerative disorders, adult onset v2.70 DCTN1 Ivone Leong Phenotypes for gene: DCTN1 were changed from Neuropathy, distal hereditary motor, type VIIB, 607641; Perry syndrome; Neuropathy, distal hereditary motor, type VIIB; Perry syndrome, 168605; {Amyotrophic lateral sclerosis, susceptibility to}, 105400 to Neuropathy, distal hereditary motor, type VIIB, OMIM:607641; Perry syndrome, OMIM:168605; {Amyotrophic lateral sclerosis, susceptibility to}, OMIM:105400
Neurodegenerative disorders, adult onset v2.69 DCTN1 Ivone Leong Publications for gene: DCTN1 were set to 26954557; 25109764; 20437543; 24343258; 27132499; 20945553 (Gene Reviews); 27346608; 19136952
Neurodegenerative disorders, adult onset v2.68 DARS2 Ivone Leong Phenotypes for gene: DARS2 were changed from Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, 611105 to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, OMIM:611105
Neurodegenerative disorders, adult onset v2.67 CYP7B1 Ivone Leong Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive to Spastic paraplegia 5A, autosomal recessive, OMIM:270800
Neurodegenerative disorders, adult onset v2.66 CYP27A1 Ivone Leong Phenotypes for gene: CYP27A1 were changed from Cerebrotendinous xanthomatosis, 213700; progressive lower extremity spasticity,often disproportionate to any degree of weakness to Cerebrotendinous xanthomatosis, OMIM:213700; progressive lower extremity spasticity,often disproportionate to any degree of weakness
Neurodegenerative disorders, adult onset v2.65 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Ceroid lipofuscinosis, neuronal, 13, Kufs type 615362 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362
Neurodegenerative disorders, adult onset v2.64 CSF1R Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy;Dementia;diffuse leukoencephalopathy with spheroids
Neurodegenerative disorders, adult onset v2.64 CSF1R Ivone Leong Phenotypes for gene: CSF1R were changed from dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy; Dementia; diffuse leukoencephalopathy with spheroids to dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy; Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820
Neurodegenerative disorders, adult onset v2.63 CP Ivone Leong Phenotypes for gene: CP were changed from Dystonia; Aceruloplasminemia; Cerebellar ataxia, 604290; Hemosiderosis, systemic, due to aceruloplasminemia, 604290 to Dystonia; Cerebellar ataxia, OMIM:604290; Hemosiderosis, systemic, due to aceruloplasminemia, OMIM:604290
Neurodegenerative disorders, adult onset v2.62 COASY Ivone Leong Phenotypes for gene: COASY were changed from COASY protein-associated neurodegeneration; Neurodegeneration with brain iron accumulation 6 to COASY protein-associated neurodegeneration; Neurodegeneration with brain iron accumulation 6, OMIM:615643
Neurodegenerative disorders, adult onset v2.61 CLN6 Ivone Leong Phenotypes for gene: CLN6 were changed from Ceroid lipofuscinosis, neuronal, 6, 601780; Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, 204300 to Ceroid lipofuscinosis, neuronal, 6, OMIM:601780; Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, OMIM:204300
Neurodegenerative disorders, adult onset v2.60 CLCN2 Ivone Leong Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; Leukoencephalopathy with ataxia, 615651 to {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; Leukoencephalopathy with ataxia, OMIM:615651
Neurodegenerative disorders, adult onset v2.59 CHMP2B Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
familial frontotemporal lobar degeneration (ALS17);Dystonia;Frontotemporal Dementia;Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Dementia, familial, nonspecific, 600795;Dementia, familial, nonspecific, 600795Amyotrophic lateral sclerosis 17, 614696;Amyotrophic lateral sclerosis 17, 614696
Neurodegenerative disorders, adult onset v2.59 CHMP2B Ivone Leong Phenotypes for gene: CHMP2B were changed from familial frontotemporal lobar degeneration (ALS17); Dystonia; Frontotemporal Dementia; Frontotemporal dementia and/or amyotrophic lateral sclerosis 1; Dementia, familial, nonspecific, 600795; Dementia, familial, nonspecific, 600795Amyotrophic lateral sclerosis 17, 614696; Amyotrophic lateral sclerosis 17, 614696 to Frontotemporal dementia and/or amytrophic lateral sclerosis 7, OMIM:600795; Dystonia
Neurodegenerative disorders, adult onset v2.58 CHCHD2 Ivone Leong Phenotypes for gene: CHCHD2 were changed from Parkinson disease 22, autosomal dominant; 616710 to Parkinson disease 22, autosomal dominant, OMIM:616710
Neurodegenerative disorders, adult onset v2.57 CHCHD2 Ivone Leong Publications for gene: CHCHD2 were set to Funayama, M., Ohe, K., Amo, T., Furuya, N., Yamaguchi, J., Saiki, S., Li, Y., Ogaki, K., Ando, M., Yoshino, H., Tomiyama, H., Nishioka, K., and 12 others. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 14: 274-282, 2015; 25662902; 26067114; 26705026; 26067110
Neurodegenerative disorders, adult onset v2.56 CHCHD10 Ivone Leong Phenotypes for gene: CHCHD10 were changed from ?Myopathy, isolated mitochondrial, autosomal dominant, 616209 to ?Myopathy, isolated mitochondrial, autosomal dominant, OMIM:616209
Neurodegenerative disorders, adult onset v2.55 CCNF Ivone Leong Phenotypes for gene: CCNF were changed from Frontotemporal dementia / amyotrophic lateral sclerosis to Frontotemporal dementia and/or amyotrophic lateral sclerosis 5, OMIM:619141
Neurodegenerative disorders, adult onset v2.54 CACNA1G Ivone Leong Phenotypes for gene: CACNA1G were changed from Spinocerebellar ataxia 42, 61679 to Spinocerebellar ataxia 42, OMIM:616795
Dystonia, chorea or related movement disorder, adult onset v1.42 DCTN1 Arina Puzriakova Phenotypes for gene: DCTN1 were changed from Perry syndrome to Perry syndrome, OMIM:168605; Neuronopathy, distal hereditary motor, type VIIB, OMIM:607641
Neurodegenerative disorders, adult onset v2.53 C19orf12 Ivone Leong Phenotypes for gene: C19orf12 were changed from mitochondrial membrane protein-associated neurodegeneration; Dystonia; neurodegeneration with brain iron accumulation-4; Neurodegeneration with brain iron accumulation 4 to Dystonia; neurodegeneration with brain iron accumulation-4, OMIM:614298
Neurodegenerative disorders, adult onset v2.52 ATP7B Ivone Leong Phenotypes for gene: ATP7B were changed from Wilson disease 277900; Dystonia; Wilson Disease to Wilson disease, OMIM: 277900; Dystonia
Dystonia, chorea or related movement disorder, adult onset v1.41 DCAF17 Arina Puzriakova Phenotypes for gene: DCAF17 were changed from Woodhouse-Sakati syndrome; Dystonia to Woodhouse-Sakati syndrome, OMIM:241080
Neurodegenerative disorders, adult onset v2.51 ATP1A3 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
ALTERNATING HEMIPLEGIA OF CHILDHOOD 2, 614820;CAPOS syndrome;DYSTONIA 12, 128235;Dystonia-12;alternating hemiplegia of childhood;Dystonia-12, 128235;Rapid-Onset Dystonia-Parkinsonism;rapid-onset dystonia-parkinsonism;Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS, #601338);Alternating hemiplegia of childhood 2 (#614820) and Dystonia 12 (#128235)
Neurodegenerative disorders, adult onset v2.51 ATP1A3 Ivone Leong Phenotypes for gene: ATP1A3 were changed from ALTERNATING HEMIPLEGIA OF CHILDHOOD 2, 614820; CAPOS syndrome; DYSTONIA 12, 128235; Dystonia-12; alternating hemiplegia of childhood; Dystonia-12, 128235; Rapid-Onset Dystonia-Parkinsonism; rapid-onset dystonia-parkinsonism; Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS, #601338); Alternating hemiplegia of childhood 2 (#614820) and Dystonia 12 (#128235) to ALTERNATING HEMIPLEGIA OF CHILDHOOD 2, OMIM:614820; CAPOS syndrome, OMIM:601338; DYSTONIA 12, OMIM:128235; Rapid-Onset Dystonia-Parkinsonism
Neurodegenerative disorders, adult onset v2.50 ATP13A2 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Parkinson disease 9, 606693;Dystonia;Kufor-Rakeb syndrome;Kufor-Rakeb Syndrome;Parkinson disease;Adult-onset lower-limb predominant spastic paraparesis;Spastic paraplegia 78, autosomal recessive, 617225;complicated hereditary spastic paraplegia
Neurodegenerative disorders, adult onset v2.50 ATP13A2 Ivone Leong Phenotypes for gene: ATP13A2 were changed from Parkinson disease 9, 606693; Dystonia; Kufor-Rakeb syndrome; Kufor-Rakeb Syndrome; Parkinson disease; Adult-onset lower-limb predominant spastic paraparesis; Spastic paraplegia 78, autosomal recessive, 617225; complicated hereditary spastic paraplegia to Kufor-Rakeb syndrome, OMIM:606693; Dystonia; Spastic paraplegia 78, autosomal recessive, OMIM:617225
Neurodegenerative disorders, adult onset v2.49 ARSA Ivone Leong Phenotypes for gene: ARSA were changed from Metachromatic leukodystrophy (#250100); Dystonia to Metachromatic leukodystrophy, OMIM:250100; Dystonia
Neurodegenerative disorders, adult onset v2.48 APP Ivone Leong Phenotypes for gene: APP were changed from Alzheimer disease 1, familial OMIM:104300; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants OMIM:605714 to Alzheimer disease 1, familial, OMIM:104300; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants, OMIM:605714
Neurodegenerative disorders, adult onset v2.47 ANXA11 Ivone Leong Phenotypes for gene: ANXA11 were changed from Amytrophic lateral sclerosis 23; 617839 to Amytrophic lateral sclerosis 23, OMIM:617839
Neurodegenerative disorders, adult onset v2.46 ANG Ivone Leong Phenotypes for gene: ANG were changed from Amyotrophic lateral sclerosis 9, 611895; Amyotrophic Lateral Sclerosis, Dominant; familial amyotrophic lateral sclerosis (ALS9) to Amyotrophic lateral sclerosis 9, 611895
Neurodegenerative disorders, adult onset v2.45 ALS2 Ivone Leong Phenotypes for gene: ALS2 were changed from Primary lateral sclerosis, juvenile, 606353; Spastic paralysis, infantile onset ascending, 607225; Amyotrophic lateral sclerosis 2, juvenile, 205100; Amyotrophic Lateral Sclerosis, Recessive to Primary lateral sclerosis, juvenile, 606353; Spastic paralysis, infantile onset ascending, 607225; Amyotrophic lateral sclerosis 2, juvenile, 205100
Dystonia, chorea or related movement disorder, adult onset v1.40 CYP27A1 Arina Puzriakova Phenotypes for gene: CYP27A1 were changed from Cerebrotendinous xanthomatosis, CTX, 213700; Dystonia; Dystonia, including childhood & adult onset to Cerebrotendinous xanthomatosis, OMIM:213700
Dystonia, chorea or related movement disorder, adult onset v1.39 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to 23787135
Dystonia, chorea or related movement disorder, adult onset v1.38 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy; diffuse leukoencephalopathy with spheroids to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820
Neurodegenerative disorders, adult onset v2.44 AFG3L2 Ivone Leong Phenotypes for gene: AFG3L2 were changed from Spinocerebellar ataxia 28; Spinocerebellar Ataxia, Dominant; Ataxia, spastic, 5, autosomal recessive; Dystonia; Spastic ataxia 5, autosomal recessive to Spinocerebellar ataxia 28, OMIM:610246; Ataxia, spastic, 5, autosomal recessive, OMIM:614487; Dystonia
Dystonia, chorea or related movement disorder, adult onset v1.37 CP Arina Puzriakova Phenotypes for gene: CP were changed from Cerebellar ataxia 604290; Aceruloplasminemia; Hypoceruloplasminemia, hereditary 604290; Dystonia; Hemosiderosis, systemic, due to aceruloplasminemia 604290 to Cerebellar ataxia, OMIM:604290; Hypoceruloplasminemia, hereditary, OMIM:604290; Hemosiderosis, systemic, due to aceruloplasminemia, OMIM:604290
Neurodegenerative disorders, adult onset v2.43 ABCD1 Ivone Leong Phenotypes for gene: ABCD1 were changed from Hereditary spastic paraplegia; adrenal failure; VLCFA accumulation; spastic paraparesis to Hereditary spastic paraplegia, MONDO:0019064; adrenal failure; VLCFA accumulation; spastic paraparesis
Dystonia, chorea or related movement disorder, adult onset v1.36 CHMP2B Arina Puzriakova Phenotypes for gene: CHMP2B were changed from familial frontotemporal lobar degeneration (ALS17); Dystonia; Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 7, OMIM:600795
Hydrocephalus v2.99 WNT3 Ivone Leong Phenotypes for gene: WNT3 were changed from Tetra-amelia syndrome to ?Tetra-amelia syndrome 1, OMIM:273395
Hydrocephalus v2.98 TBC1D7 Ivone Leong Phenotypes for gene: TBC1D7 were changed from Macrocephaly/megalencephaly syndrome, autosomal recessive to Macrocephaly/megalencephaly syndrome, autosomal recessive, OMIM:248000
Dystonia, chorea or related movement disorder, adult onset v1.35 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from familial hemiplegic migraine type 1, 141500; episodic ataxia type 2 (EA2),108500 to Episodic ataxia, type 2, OMIM:108500; Spinocerebellar ataxia 6, OMIM:183086; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Hydrocephalus v2.97 SEC24D Ivone Leong Phenotypes for gene: SEC24D were changed from Cole-Carpenter syndrome 2 to Cole-Carpenter syndrome 2, OMIM:616294
Hydrocephalus v2.96 SEC24D Ivone Leong Publications for gene: SEC24D were set to 25683121
Hydrocephalus v2.95 PTCH2 Ivone Leong Phenotypes for gene: PTCH2 were changed from Basal cell nevus syndrome to Basal cell nevus syndrome, OMIM:109400
Hydrocephalus v2.94 P4HB Ivone Leong Phenotypes for gene: P4HB were changed from Cole-Carpenter syndrome 1 to Cole-Carpenter syndrome 1, OMIM:112240
Hydrocephalus v2.93 P4HB Ivone Leong Publications for gene: P4HB were set to 25683117
Hydrocephalus v2.92 MTM1 Ivone Leong Phenotypes for gene: MTM1 were changed from Myotubular myopathy, X-linked to Myotubular myopathy, X-linked, OMIM:310400
Hydrocephalus v2.91 MPDZ Ivone Leong Phenotypes for gene: MPDZ were changed from Hydrocephalus, nonsyndromic, autosomal recessive 2, OMIM:615219 to Hydrocephalus, congenital, 2, with or without brain or eye anomalies, OMIM:615219
Hydrocephalus v2.90 MPDZ Ivone Leong Phenotypes for gene: MPDZ were changed from Hydrocephalus, nonsyndromic, autosomal recessive 2 615219 to Hydrocephalus, nonsyndromic, autosomal recessive 2, OMIM:615219
Hydrocephalus v2.89 KIF7 Ivone Leong Phenotypes for gene: KIF7 were changed from ?Hydrolethalus syndrome 2 614120 to ?Hydrolethalus syndrome 2, OMIM:614120
Hydrocephalus v2.88 HDAC6 Ivone Leong Phenotypes for gene: HDAC6 were changed from ?Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia to ?Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia, OMIM:300863
Hydrocephalus v2.87 FLNA Ivone Leong Phenotypes for gene: FLNA were changed from Otopalatodigital syndrome, type II to Otopalatodigital syndrome, type II, OMIM:304120
Hydrocephalus v2.86 EBP Ivone Leong Phenotypes for gene: EBP were changed from MEND syndrome to MEND syndrome, OMIM:300960
Hydrocephalus v2.85 CLIC2 Ivone Leong Phenotypes for gene: CLIC2 were changed from ?Mental retardation, X-linked, syndromic 32 to ?Mental retardation, X-linked, syndromic 32, OMIM:300886
Hydrocephalus v2.84 B3GNT2 Ivone Leong Phenotypes for gene: B3GNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 13 615287 to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13, MONDO:0014120
Hydrocephalus v2.83 ARX Ivone Leong Phenotypes for gene: ARX were changed from Hydranencephaly with abnormal genitalia to Hydranencephaly with abnormal genitalia, OMIM:300215
Hydrocephalus v2.82 ZIC3 Ivone Leong Phenotypes for gene: ZIC3 were changed from VACTERL association, X-linked to VACTERL association, X-linked, OMIM:314390
Hydrocephalus v2.81 ZIC2 Ivone Leong Phenotypes for gene: ZIC2 were changed from Holoprosencephaly 5 to Holoprosencephaly 5, OMIM:609637
Hydrocephalus v2.80 ZBTB20 Ivone Leong Phenotypes for gene: ZBTB20 were changed from Primrose syndrome to Primrose syndrome, OMIM:259050
Hydrocephalus v2.79 WASHC5 Ivone Leong Phenotypes for gene: WASHC5 were changed from Ritscher-Schinzel syndrome 1 to Ritscher-Schinzel syndrome 1, OMIM:220210
Hydrocephalus v2.78 USP9X Ivone Leong Phenotypes for gene: USP9X were changed from Mental retardation, X-linked 99 300919 XLR; Mental retardation, X-linked 99, syndromic, female-restricted 300968 to Mental retardation, X-linked 99, OMIM:300919; Mental retardation, X-linked 99, syndromic, female-restricted OMIM:300968
Neurological segmental overgrowth v1.15 PIK3CA Arina Puzriakova Phenotypes for gene: PIK3CA were changed from CLAPO syndrome, somatic, OMIM:613089; CLOVE syndrome, somatic, OMIM:612918; Macrodactyly, somatic, OMIM:155500; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501 to Cowden syndrome 5, OMIM:615108; CLAPO syndrome, somatic, OMIM:613089; CLOVE syndrome, somatic, OMIM:612918; Macrodactyly, somatic, OMIM:155500; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501
Neurological segmental overgrowth v1.14 PTEN Arina Puzriakova Phenotypes for gene: PTEN were changed from hemihypertrophy; Bannayan Riley Ruvalcalba Syndrome; Bannayan-Riley-Ruvalcaba Syndrome; Proteus-like syndrome; macrocephaly; Bannayan-Riley-Ruvalcaba syndrome, 153480; BRRS; Bannayan-Riley-Ruvalcaba syndrome,153480; megalencephaly; PTEN Hamartoma Tumor Syndrome; Macrocephaly and Overgrowth Syndromes; PHTS; Cowden syndrome to Cowden syndrome 1, OMIM:158350; Lhermitte-Duclos syndrome, OMIM:158350; Macrocephaly/autism syndrome, OMIM:605309
Neurological segmental overgrowth v1.13 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from MPPH1; Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, 603387; Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 603387; Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome 1; Macrocephaly and Overgrowth Syndromes to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Neurological segmental overgrowth v1.12 PIK3CA Arina Puzriakova Phenotypes for gene: PIK3CA were changed from Megalencephaly-capillary malformation-polymicrogyria syndrome, 602501; CLOVE syndrome; CLOVES; congenital lipomatous overgrowth, vascular malformations, and epidermal nevi, 612918; Congenital Lipomatous Overgrowth Vascular Malformations, Epidermal Nevi and Scoliosis/Skeletal/Spinal anomalies syndrome; CLOVES syndrome; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic; Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi; Megalencephaly-Capillary Malformation- Polymicrogyria Syndrome; macrocephaly-capillary malformation (MCM) syndrome; Megalencephaly-Capillary malformation syndrome; Macrocephaly and Overgrowth Syndromes; MCAP to CLAPO syndrome, somatic, OMIM:613089; CLOVE syndrome, somatic, OMIM:612918; Macrodactyly, somatic, OMIM:155500; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501
Neurological segmental overgrowth v1.11 CCND2 Arina Puzriakova Phenotypes for gene: CCND2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, 615938; MPPH3; Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome 3 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, OMIM:615938
Neurological segmental overgrowth v1.10 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, 615937; Macrocephaly and Overgrowth Syndromes; MPPH2; Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome 2 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937; Macrocephaly and Overgrowth Syndromes
Neurological segmental overgrowth v1.9 AKT1 Arina Puzriakova Phenotypes for gene: AKT1 were changed from Proteus syndrome, 176920; Proteus syndrome, somatic,176920; Macrocephaly and Overgrowth Syndromes; Segmental Overgrowth Syndrome; Proteus syndrome to Proteus syndrome, somatic, OMIM:176920; Macrocephaly and Overgrowth Syndromes; Segmental Overgrowth Syndrome; Proteus syndrome
Paediatric or syndromic cardiomyopathy v1.19 MIB1 Zornitza Stark reviewed gene: MIB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23314057; Phenotypes: Left ventricular noncompaction 7, MIM# 615092, cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hydrocephalus v2.77 TWIST1 Ivone Leong Phenotypes for gene: TWIST1 were changed from Saethre-Chotzen syndrome 101400 to Saethre-Chotzen syndrome with or without eyelid anomalies, OMIM:101400
Hydrocephalus v2.76 TMEM5 Ivone Leong Phenotypes for gene: TMEM5 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10 615041 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, OMIM:615041
Hydrocephalus v2.75 TCF12 Ivone Leong Phenotypes for gene: TCF12 were changed from Craniosynostosis 3 615314 to Craniosynostosis 3, OMIM:615314
Hydrocephalus v2.74 SUMF1 Ivone Leong Phenotypes for gene: SUMF1 were changed from Multiple sulfatase deficiency 272200 to Multiple sulfatase deficiency, OMIM:272200
Hydrocephalus v2.73 SUFU Ivone Leong Phenotypes for gene: SUFU were changed from Basal cell nevus syndrome to Basal cell nevus syndrome, OMIM:109400
Hydrocephalus v2.72 STRADA Ivone Leong Phenotypes for gene: STRADA were changed from Polyhydramnios, megalencephaly, and symptomatic epilepsy, 611087 to Polyhydramnios, megalencephaly, and symptomatic epilepsy, OMIM:611087
Hydrocephalus v2.71 SNX10 Ivone Leong Phenotypes for gene: SNX10 were changed from Osteopetrosis, autosomal recessive 8 to Osteopetrosis, autosomal recessive 8, OMIM:615085