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Intellectual disability v3.265 PPP1R12A Arina Puzriakova changed review comment from: PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.; to: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.42 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Monogenic hearing loss v2.42 MN1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - added to this panel following suggestion from the clinical team.
Monogenic hearing loss v2.42 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.41 MN1 Arina Puzriakova gene: MN1 was added
gene: MN1 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: MN1.
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Review for gene: MN1 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum). 20/25 individuals had conductive and/or sensorineural hearing loss (no report on hearing status in a further 6 individuals across the two studies).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect.
Sources: Literature
Laterality disorders and isomerism v1.11 MNS1 Ivone Leong Classified gene: MNS1 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.11 MNS1 Ivone Leong Added comment: Comment on list classification: This gene has been added as an Amber gene and will be promoted to a Green gene at the next major update. It has been tagged with "for-review".
Laterality disorders and isomerism v1.11 MNS1 Ivone Leong Gene: mns1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.10 MNS1 Ivone Leong reviewed gene: MNS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.10 MNS1 Ivone Leong Tag for-review tag was added to gene: MNS1.
Laterality disorders and isomerism v1.10 MNS1 Ivone Leong Publications for gene: MNS1 were set to 31534215; 30148830
Malformations of cortical development v2.9 MN1 Arina Puzriakova changed review comment from: Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature; to: Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Malformations of cortical development v2.9 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Malformations of cortical development v2.9 MN1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - added to this panel following suggestion from the clinical team.
Malformations of cortical development v2.9 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.8 MN1 Arina Puzriakova gene: MN1 was added
gene: MN1 was added to Malformations of cortical development. Sources: Literature
for-review tags were added to gene: MN1.
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Review for gene: MN1 was set to GREEN
Added comment: Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Infantile enterocolitis & monogenic inflammatory bowel disease v1.18 ANO1 Arina Puzriakova Classified gene: ANO1 as Amber List (moderate evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.18 ANO1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases and review of phenotype associated with variants in this gene.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.18 ANO1 Arina Puzriakova Gene: ano1 has been classified as Amber List (Moderate Evidence).
Infantile enterocolitis & monogenic inflammatory bowel disease v1.17 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Phenotypes for gene: ANO1 were set to Impaired intestinal peristalsis; Haemorrhagic diarrhoea; Dysmorphic features
Review for gene: ANO1 was set to AMBER
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Intestinal failure or congenital diarrhoea v1.5 ANO1 Arina Puzriakova Classified gene: ANO1 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.5 ANO1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases and review of phenotype associated with variants in this gene.
Intestinal failure or congenital diarrhoea v1.5 ANO1 Arina Puzriakova Gene: ano1 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.4 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Phenotypes for gene: ANO1 were set to Impaired intestinal peristalsis; Haemorrhagic diarrhoea; Dysmorphic features
Review for gene: ANO1 was set to AMBER
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Laterality disorders and isomerism v1.9 MNS1 Ivone Leong Phenotypes for gene: MNS1 were changed from Heterotaxy; male infertility to Heterotaxy, visceral, 9, autosomal, with male infertility, 618948
Arrhythmogenic right ventricular cardiomyopathy v2.9 CDH2 Ivone Leong commented on gene: CDH2: Tagged with "for-review" for the specialist group to review whether this gene should remain Green.
Arrhythmogenic right ventricular cardiomyopathy v2.9 CDH2 Ivone Leong Tag for-review tag was added to gene: CDH2.
Parkinson Disease and Complex Parkinsonism v1.68 COASY Zornitza Stark gene: COASY was added
gene: COASY was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COASY were set to 28489334; 24360804
Phenotypes for gene: COASY were set to Neurodegeneration with brain iron accumulation 6, MIM# 615643
Review for gene: COASY was set to AMBER
Added comment: Extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism are prominent due to iron accumulation in the basal ganglia. 2 families reported.
Sources: Expert list
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Classified gene: DDC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Added comment: Comment on list classification: This is a metabolic gene and is green on the Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/DDC/), therefore it is rated as amber on the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Gene: ddc has been classified as Amber List (Moderate Evidence).
Parkinson Disease and Complex Parkinsonism v1.68 CLN3 Zornitza Stark gene: CLN3 was added
gene: CLN3 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: CLN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN3 were set to 19489875; 11342698
Phenotypes for gene: CLN3 were set to Ceroid lipofuscinosis, neuronal, 3 MIM#204200
Review for gene: CLN3 was set to GREEN
gene: CLN3 was marked as current diagnostic
Added comment: Parkinsonism is a prominent feature of this condition.
Sources: Expert list
Early onset or syndromic epilepsy v2.143 DDC Sarah Leigh Tag for-review tag was added to gene: DDC.
Optic neuropathy v2.27 AFG3L2 Ivone Leong reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Parkinson Disease and Complex Parkinsonism v1.68 CHCHD2 Zornitza Stark reviewed gene: CHCHD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32068847, 25662902, 31600778, 26705026; Phenotypes: Parkinson disease 22, autosomal dominant MIM#616710; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Optic neuropathy v2.27 AFG3L2 Ivone Leong Tag for-review tag was added to gene: AFG3L2.
Optic neuropathy v2.27 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to 29181157; 26539208; 30544562; 30252181; 30389403; 30252181; 30389403; 32219868
Parkinson Disease and Complex Parkinsonism v1.68 ATP7B Zornitza Stark gene: ATP7B was added
gene: ATP7B was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: ATP7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP7B were set to 17435591
Phenotypes for gene: ATP7B were set to Wilson disease MIM#277900
Review for gene: ATP7B was set to GREEN
gene: ATP7B was marked as current diagnostic
Added comment: Parkinsonism is a prominent neurological feature of Wilson disease.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 TRIM22 Zornitza Stark gene: TRIM22 was added
gene: TRIM22 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: TRIM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM22 were set to 26836588
Phenotypes for gene: TRIM22 were set to Inflammatory bowel disease
Review for gene: TRIM22 was set to GREEN
gene: TRIM22 was marked as current diagnostic
Added comment: Three unrelated families reported with bi-allelic variants in this gene, and very early onset IBD, some functional data.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 RIPK1 Zornitza Stark gene: RIPK1 was added
gene: RIPK1 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: RIPK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK1 were set to 30026316; 30591564; 31213653
Phenotypes for gene: RIPK1 were set to Immunodeficiency 57, MIM#618108
Review for gene: RIPK1 was set to GREEN
Added comment: Ten families reported, inflammatory bowel disease/enteropathy is a common feature of this immune dysregulation syndrome.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 NOD2 Zornitza Stark gene: NOD2 was added
gene: NOD2 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: NOD2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NOD2 were set to 11385576; 17804789; 32463623
Phenotypes for gene: NOD2 were set to {Inflammatory bowel disease 1, Crohn disease} 266600; {Yao syndrome} 617321
Review for gene: NOD2 was set to GREEN
gene: NOD2 was marked as current diagnostic
Added comment: Variants in NOD2 (particularly bi-allelic ones) are associated with increased risk of Crohn's disease. 7% of a cohort of 401 patients with Crohn's had NOD2 bi-allelic variants.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 FERMT1 Zornitza Stark reviewed gene: FERMT1: Rating: RED; Mode of pathogenicity: None; Publications: 19057668, 27537055, 32463623; Phenotypes: Kindler syndrome, MIM# 173650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.26 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to 29181157; 26539208; 30544562; 30252181; 30389403; 30252181; 30389403
Optic neuropathy v2.25 AFG3L2 Ivone Leong Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive, 614487; Spinocerebellar ataxia 28, 610246 to Optic atrophy 12, 618977
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 BACH2 Zornitza Stark gene: BACH2 was added
gene: BACH2 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: BACH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BACH2 were set to 28530713
Phenotypes for gene: BACH2 were set to Immunodeficiency 60, MIM# 618394; inflammatory bowel disease; recurrent sinopulmonary infections
Review for gene: BACH2 was set to GREEN
Added comment: Two families and a mouse model.
Sources: Expert list
Hypertrophic cardiomyopathy v2.8 ATAD3A Ivone Leong Classified gene: ATAD3A as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.8 ATAD3A Ivone Leong Gene: atad3a has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.7 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
watchlist tags were added to gene: ATAD3A.
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307; 28652416; 28158749; 31727539
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to AMBER
Added comment: Added new gene as Amber based on the available literature. As not every patient with a monoallelic/biallelic variant in this gene presented with HCM, this gene has been rated Amber until further evidence is available.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have HCM. The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.
Sources: Literature
Optic neuropathy v2.24 ATAD3A Ivone Leong Tag watchlist tag was added to gene: ATAD3A.
Bilateral congenital or childhood onset cataracts v2.11 ATAD3A Ivone Leong Classified gene: ATAD3A as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.11 ATAD3A Ivone Leong Gene: atad3a has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.10 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Cataracts. Sources: Literature
for-review tags were added to gene: ATAD3A.
Mode of inheritance for gene: ATAD3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307; 28652416; 28158749; 31727539
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to AMBER
Added comment: Added new gene as Amber for now, but should be promoted to Green (as there is enough evidence for it to be a Green gene) at the next major review.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have hypertrophic cardiomyopathy (HCM). The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.15 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATAD3A were set to 28158749
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to RED
Added comment: Added as a Red gene based on the available literature. There is only one case. PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.
Sources: Literature
Optic neuropathy v2.24 ATAD3A Ivone Leong Classified gene: ATAD3A as Amber List (moderate evidence)
Optic neuropathy v2.24 ATAD3A Ivone Leong Added comment: Comment on list classification: Promoted gene from Red to Amber based on the available literature. As not every patient with a monoallelic variant in this gene presented with optic atrophy, this gene has been rated Amber until further evidence is available.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have hypertrophic cardiomyopathy (HCM). The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.
Optic neuropathy v2.24 ATAD3A Ivone Leong Gene: atad3a has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.23 ATAD3A Ivone Leong Publications for gene: ATAD3A were set to 27640307; 28652416
Intellectual disability v3.265 TRNT1 Arina Puzriakova Tag for-review tag was added to gene: TRNT1.
Intellectual disability v3.265 TRNT1 Arina Puzriakova Publications for gene: TRNT1 were set to 25193871; 23553769; 29170023; 27389523
Intellectual disability v3.264 TRNT1 Arina Puzriakova Classified gene: TRNT1 as Amber List (moderate evidence)
Intellectual disability v3.264 TRNT1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - sufficient number of cases with (mild-profound) developmental delay, associated with biallelic variants in TRNT1.
Intellectual disability v3.264 TRNT1 Arina Puzriakova Gene: trnt1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.7 B4GAT1 Zornitza Stark reviewed gene: B4GAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359570, 23877401, 23359570, 23217742; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 13 MIM# 615287; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Malformations of cortical development v2.7 ATP1A2 Zornitza Stark gene: ATP1A2 was added
gene: ATP1A2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 31608932
Phenotypes for gene: ATP1A2 were set to hydrops fetalis; microcephaly; arthrogryposis; extensive cortical malformations
Review for gene: ATP1A2 was set to GREEN
gene: ATP1A2 was marked as current diagnostic
Added comment: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities including extensive cortical malformations. Mouse model is perinatal lethal. This is a distinct phenotype from the mono allelic variants associated with alternating hemiplegia.
Sources: Expert list
Malformations of cortical development v2.7 ARF1 Zornitza Stark gene: ARF1 was added
gene: ARF1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, MIM# 618185
Review for gene: ARF1 was set to GREEN
gene: ARF1 was marked as current diagnostic
Added comment: Three unrelated individuals reported with de novo missense in this gene.
Sources: Expert list
Malformations of cortical development v2.7 APC2 Zornitza Stark gene: APC2 was added
gene: APC2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108
Phenotypes for gene: APC2 were set to Cortical dysplasia, complex, with other brain malformations 10, MIM#618677
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: 12 individuals from 8 unrelated families; intellectual disability, seizures, cortical dysplasia including posterior to anterior predominant pattern of lissencephaly, heterotopias, paucity of white matter, thin corpus callosum.
Sources: Expert list
Structural eye disease v1.9 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ocular coloboma v1.38 TENM3 Arina Puzriakova Publications for gene: TENM3 were set to 22766609, 27103084, 24859618
Ocular coloboma v1.37 TENM3 Arina Puzriakova Classified gene: TENM3 as Green List (high evidence)
Ocular coloboma v1.37 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Green List (High Evidence).
Ocular coloboma v1.36 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.28 TENM3 Arina Puzriakova Phenotypes for gene: TENM3 were changed from Microphthalmia isolated with coloboma 9 to Microphthalmia, syndromic 15, 615145; ?Microphthalmia, isolated, with coloboma 9, 615145
Anophthalmia or microphthalmia v1.27 TENM3 Arina Puzriakova Mode of inheritance for gene: TENM3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.26 TENM3 Arina Puzriakova Classified gene: TENM3 as Green List (high evidence)
Anophthalmia or microphthalmia v1.26 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Green List (High Evidence).
Malformations of cortical development v2.7 CRADD Zornitza Stark gene: CRADD was added
gene: CRADD was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: CRADD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRADD were set to 27773430
Phenotypes for gene: CRADD were set to Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499
Review for gene: CRADD was set to GREEN
gene: CRADD was marked as current diagnostic
Added comment: At least 5 families reported though some were from the Pennsylvania Mennonite population, and had same founder variant (but at least 4 unique variants reported). Brain imaging shows a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex.
Sources: Expert list
Anophthalmia or microphthalmia v1.25 TENM3 Arina Puzriakova changed review comment from: PMID: 22766609 (2012) - Two affected sibs from a consanguineous Saudi family, with nonsyndromic bilateral microphthalmia, iris and retinal coloboma, and microcornea. Normal cognitive development was noted in both sibs. A homozygous 1 bp insertion (c.2083dup, p.T695Nfs*5) in the TENM3 gene, causing a frameshift predicted to result in premature truncation of the resulting protein, segregated with the phenotype. No other pathogenic variant were identified in any of the known microphthalmia genes.

PMID: 27103084 (2016) - In a patient with bilateral colobomatous microphthalmia authors identified a segregating homozygous splice site variant (c.2968‐2A>T, p.Val990Cysfs*13) in the TENM3 gene. His development was delayed, and he entered a specialised institution at the age of eight because of his apparent ID.

PMID: 30513139 (2018) - In two sisters with ocular coloboma and microcornea, but without microphthalmia, WES revealed a homozygous TENM3 variant (c.1857T>A, p. Cys619*). Sanger sequencing confirmed the parents were heterozygous carriers. Patient cells were not available for functional study of the variant. The older child (5.5 years old) was said to have global developmental delay; while the younger child (4 years 3 months old) had mild motor delay and spoke only few words, but cognition was reported normal.

PMID: 29753094 (2019) - 9-year-old boy with right eye microphthalmia, sclerocornea of both eyes, anterior segment dysgenesis, and severe global developmental delay, associated with compound heterozygous variants ([c.4046C>G, p.Ala1349Gly] ; [c.7687C>T, p.Arg2563Trp]) in the TENM3 gene. The p.Ala1349Gly variant was found in a heterozygous state in the proband's unaffected father and brother; however, the p.Arg2563Trp variant was not present in either parent, suggesting mosaicism in the mother or a de novo occurrence in the proband.; to: Associated with phenotype in OMIM, and a probable gene for Colobomatous microphthalmia in G2P.

PMID: 22766609 (2012) - Two affected sibs from a consanguineous Saudi family, with nonsyndromic bilateral microphthalmia, iris and retinal coloboma, and microcornea. Normal cognitive development was noted in both sibs. A homozygous 1 bp insertion (c.2083dup, p.T695Nfs*5) in the TENM3 gene, causing a frameshift predicted to result in premature truncation of the resulting protein, segregated with the phenotype. No other pathogenic variant were identified in any of the known microphthalmia genes.

PMID: 27103084 (2016) - In a patient with bilateral colobomatous microphthalmia authors identified a segregating homozygous splice site variant (c.2968‐2A>T, p.Val990Cysfs*13) in the TENM3 gene. His development was delayed, and he entered a specialised institution at the age of eight because of his apparent ID.

PMID: 30513139 (2018) - In two sisters with ocular coloboma and microcornea, but without microphthalmia, WES revealed a homozygous TENM3 variant (c.1857T>A, p. Cys619*). Sanger sequencing confirmed the parents were heterozygous carriers. Patient cells were not available for functional study of the variant. The older child (5.5 years old) was said to have global developmental delay; while the younger child (4 years 3 months old) had mild motor delay and spoke only few words, but cognition was reported normal.

PMID: 29753094 (2019) - 9-year-old boy with right eye microphthalmia, sclerocornea of both eyes, anterior segment dysgenesis, and severe global developmental delay, associated with compound heterozygous variants ([c.4046C>G, p.Ala1349Gly] ; [c.7687C>T, p.Arg2563Trp]) in the TENM3 gene. The p.Ala1349Gly variant was found in a heterozygous state in the proband's unaffected father and brother; however, the p.Arg2563Trp variant was not present in either parent, suggesting mosaicism in the mother or a de novo occurrence in the proband.
Anophthalmia or microphthalmia v1.25 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.263 TENM3 Arina Puzriakova Classified gene: TENM3 as Amber List (moderate evidence)
Intellectual disability v3.263 TENM3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - sufficient unrelated cases with an ID phenotype.
Intellectual disability v3.263 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.262 TENM3 Arina Puzriakova Tag for-review tag was added to gene: TENM3.
Intellectual disability v3.262 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: ; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Holoprosencephaly v2.5 RAD21 Zornitza Stark gene: RAD21 was added
gene: RAD21 was added to Holoprosencephaly. Sources: Literature
Mode of inheritance for gene: RAD21 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAD21 were set to 31334757
Phenotypes for gene: RAD21 were set to Holoprosencephaly; Septo-optic dysplasia
Review for gene: RAD21 was set to GREEN
gene: RAD21 was marked as current diagnostic
Added comment: Three individuals reported with variants in this gene and HPE phenotype
Sources: Literature
Holoprosencephaly v2.5 PPP1R12A Zornitza Stark gene: PPP1R12A was added
gene: PPP1R12A was added to Holoprosencephaly. Sources: Expert list
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Intellectual disability; holoprosencephaly; disorder of sex development
Review for gene: PPP1R12A was set to GREEN
gene: PPP1R12A was marked as current diagnostic
Added comment: 12 individuals reported.
Sources: Expert list
Malformations of cortical development v2.7 CDK13 Zornitza Stark reviewed gene: CDK13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, MIM# 617360; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.7 PEX7 Zornitza Stark reviewed gene: PEX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Peroxisome biogenesis disorder 9B (MIM#614879), Rhizomelic chondrodysplasia punctata, type 1 (MIM#215100); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.7 VLDLR Zornitza Stark gene: VLDLR was added
gene: VLDLR was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: VLDLR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VLDLR were set to 16080122; 18364738; 18326629; 22700954; 22973972
Phenotypes for gene: VLDLR were set to Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1 (MIM#224050)
Review for gene: VLDLR was set to GREEN
gene: VLDLR was marked as current diagnostic
Added comment: Gyral simplification/pachygyria reported in this condition.
Sources: Expert list
Neurotransmitter disorders v1.4 ALDH7A1 Zornitza Stark gene: ALDH7A1 was added
gene: ALDH7A1 was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: ALDH7A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALDH7A1 were set to Epilepsy, pyridoxine-dependent, MIM# 266100
Review for gene: ALDH7A1 was set to GREEN
gene: ALDH7A1 was marked as current diagnostic
Added comment: Well established gene-disease association, condition is considered a disorder of neurotransmitter metabolism by some expert groups: deficiency of antiquitin leads to the buildup of α-aminoadipic semialdehyde, resulting in a disruption in the activity of pyridoxine, which in turn is required for the breakdown of neurotransmitters. Metabolic findings: increased serum and CSF levels of pipecolic acid; increased serum, CSF and urinary levels of alpha-aminoadipic semialdehyde. Treatable disorder.
Sources: Expert list
Neurotransmitter disorders v1.4 PNPO Zornitza Stark gene: PNPO was added
gene: PNPO was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: PNPO was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PNPO were set to Pyridoxamine 5'-phosphate oxidase deficiency, MIM# 610090
Review for gene: PNPO was set to GREEN
Added comment: Well established gene-disease association. Pyridoxal 5′-phosphate is a co-factor in the synthesis of dopamine and serotonin. Multiple CSF abnormalities reported including decreased HVA and 5HIAA. Treatable disorder, typically manifesting as neonatal seizures.
Sources: Expert list
Neurotransmitter disorders v1.4 ALDH5A1 Zornitza Stark gene: ALDH5A1 was added
gene: ALDH5A1 was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: ALDH5A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH5A1 were set to 9683595; 14635103; 32402538
Phenotypes for gene: ALDH5A1 were set to Succinic semialdehyde dehydrogenase deficiency, MIM# 271980
Review for gene: ALDH5A1 was set to GREEN
gene: ALDH5A1 was marked as current diagnostic
Added comment: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. The clinical features include developmental delay, hypotonia, mental retardation, ataxia, seizures, hyperkinetic behavior, aggression, and sleep disturbances. Over 50 unrelated families reported.
Sources: Expert list
Neurotransmitter disorders v1.4 ABAT Zornitza Stark edited their review of gene: ABAT: Set current diagnostic: yes
Neurotransmitter disorders v1.4 ABAT Zornitza Stark gene: ABAT was added
gene: ABAT was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: ABAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABAT were set to 28411234; 27596361; 20052547; 10407778; 6148708
Phenotypes for gene: ABAT were set to GABA-transaminase deficiency, MIM# 613163
Review for gene: ABAT was set to GREEN
Added comment: Over ten families reported. Disorder is is characterised by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most individuals have profound developmental impairment and some die in infancy.
Sources: Expert list
Intellectual disability v3.262 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.143 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Clefting v2.3 KAT5 Konstantinos Varvagiannis gene: KAT5 was added
gene: KAT5 was added to Clefting. Sources: Literature
Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KAT5 were set to 32822602
Phenotypes for gene: KAT5 were set to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Mode of pathogenicity for gene: KAT5 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: KAT5 was set to AMBER
Added comment: Humbert el al (2020 - PMID: 32822602) report 3 individuals with de novo missense KAT5 variants.

Features included severe DD (3/3) and ID (2/2 - the 3rd was 18m on last examination), microcephaly (2/3), behavioral anomalies (3/3) including severe sleep disorder (3/3 - table S1 / night walking, sleep onset delay, excessive daytime sleepiness), seizures (3/3 - variable type and age of onset), brain MRI abnormalities (3/3 - CC, cerebellar atrophy each in 2 subjects, focal polymicrogyria in 1), various genitourinary anomalies (3/3). All had moderately short stature (-1.95 SD to -2.9SD). Cleft LP and submucous cleft P were observed in 2/3. Facial features included round face, flat profile, depressed nasal bridge, downturned corners of mouth and prognathism (each in at least 2 subjects).

KAT5 encodes a lysine acetyltransferase involved in gene expression, DNA repair, chromatine remodeling, apoptosis and cell proliferation. It is part of the NuA4 histone acetyltransferase (HAT) complex also called TIP60/p400 (TIP60 being another name for KAT5). Regulation by histone acetylation is important for proper development.

3 missense KAT5 SNVs were identified, one within the chromobarrel domain (aa 7-65 / NM_006388.3) and 2 in the acetyl-CoA binding domain (aa 365-420).

Following generation of K562 cells expressing either WT or variants, it was demonstrated that wt/mt KAT5 assemble normally into NuA4/TIP60 complexes. Histone acetyltransferase activity was however impaired for all variants, suggesting a partial loss of function mechanism.

As Humbert et al comment, it is possible that KAT5 haploinsufficiency does not lead to a
syndrome. Over 10 high-confidence LoF variants are listed in gnomAD. Heterozygous Kat5 ko mice have normal development, growth and fertility. Homozygous ko mice are embryonic lethal. In haploinsufficient mice, reduction of mRNA to 50% has been shown to be compensated at the protein level in adipose and/or other tissues (several studies cited).

RNA-Seq in fibroblasts from 2 affected individuals revealed dysregulation of highly relevant genes (e.g. for neurodevelopment, circadian clock, etc).

Mutations in KAT6A/B, encoding two other acetyltransferases cause neurodevelopmental disorders with features overlapping those observed in individuals with KAT5 variants (e.g. DD/ID, microcephaly, seizures, sleep disturbance, clefts, CC or genital anomalies).

Consider inclusion in the ID and epilepsy panels with green rating as well as the gene panel for clefting with amber.
Sources: Literature
Intellectual disability v3.262 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Review for gene: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Early onset or syndromic epilepsy v2.143 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Fetal anomalies v1.93 Catherine Snow Panel version has been signed off
Fetal anomalies v1.91 SRY Eleanor Williams Mode of inheritance for gene: SRY was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.90 SRY Eleanor Williams Added comment: Comment on mode of inheritance: Reverting to X-LINKED MOI as OMIM has XLD and YL inheritance listed.
Fetal anomalies v1.90 SRY Eleanor Williams Mode of inheritance for gene: SRY 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)
Osteopetrosis v0.6 Catherine Snow Panel types changed to GMS Rare Disease
Osteopetrosis v0.5 Catherine Snow Panel status changed from internal to public
Osteopetrosis v0.4 Catherine Snow List of related panels changed from to R104.4
Thrombocythaemia v0.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual
Osteopetrosis v0.3 TYROBP Eleanor Williams commented on gene: TYROBP
Osteopetrosis v0.3 TNFSF11 Eleanor Williams commented on gene: TNFSF11
Osteopetrosis v0.3 TNFRSF11A Eleanor Williams commented on gene: TNFRSF11A
Osteopetrosis v0.3 TGFB1 Eleanor Williams commented on gene: TGFB1
Osteopetrosis v0.3 TCIRG1 Eleanor Williams commented on gene: TCIRG1
Osteopetrosis v0.3 SOST Eleanor Williams commented on gene: SOST
Osteopetrosis v0.3 SNX10 Eleanor Williams commented on gene: SNX10
Osteopetrosis v0.3 RASGRP2 Eleanor Williams commented on gene: RASGRP2
Osteopetrosis v0.3 PTH1R Eleanor Williams commented on gene: PTH1R
Osteopetrosis v0.3 PLEKHM1 Eleanor Williams commented on gene: PLEKHM1
Osteopetrosis v0.3 OSTM1 Eleanor Williams commented on gene: OSTM1
Osteopetrosis v0.3 LRP5 Eleanor Williams commented on gene: LRP5
Osteopetrosis v0.3 LEMD3 Eleanor Williams commented on gene: LEMD3
Osteopetrosis v0.3 IKBKG Eleanor Williams commented on gene: IKBKG
Osteopetrosis v0.3 FERMT3 Eleanor Williams commented on gene: FERMT3
Osteopetrosis v0.3 FAM20C Eleanor Williams commented on gene: FAM20C
Osteopetrosis v0.3 CTSK Eleanor Williams commented on gene: CTSK
Osteopetrosis v0.3 CLCN7 Eleanor Williams commented on gene: CLCN7
Osteopetrosis v0.3 CA2 Eleanor Williams commented on gene: CA2
Osteopetrosis v0.3 ANKH Eleanor Williams commented on gene: ANKH
Osteopetrosis v0.3 AMER1 Eleanor Williams commented on gene: AMER1
Thrombocythaemia v0.5 Catherine Snow Panel status changed from internal to public
Fetal anomalies v1.89 SRY Eleanor Williams Added comment: Comment on mode of inheritance: Changing mode of inheritance to "Other" has this gene is on the Y chromosome.
Fetal anomalies v1.89 SRY Eleanor Williams Mode of inheritance for gene: SRY was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to Other
Thrombocythaemia v0.4 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Thrombocythaemia v0.3 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Thrombocythaemia v0.2 Arina Puzriakova List of related panels changed from to R406
Panel types changed to GMS signed-off
Thrombocythaemia v0.1 SH2B3 Arina Puzriakova Tag somatic tag was added to gene: SH2B3.
Thrombocythaemia v0.1 CALR Arina Puzriakova Tag somatic tag was added to gene: CALR.
Thrombocythaemia v0.1 CALR Arina Puzriakova reviewed gene: CALR: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thrombocythaemia v0.1 SH2B3 Arina Puzriakova reviewed gene: SH2B3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thrombocythaemia v0.1 JAK2 Arina Puzriakova reviewed gene: JAK2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thrombocythaemia v0.1 THPO Arina Puzriakova reviewed gene: THPO: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thrombocythaemia v0.1 MPL Arina Puzriakova reviewed gene: MPL: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Osteopetrosis v0.1 TYROBP Catherine Snow gene: TYROBP was added
gene: TYROBP was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TYROBP was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TYROBP were set to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 221770
Osteopetrosis v0.1 TNFSF11 Catherine Snow gene: TNFSF11 was added
gene: TNFSF11 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TNFSF11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TNFSF11 were set to Osteopetrosis, autosomal recessive 2 259710
Osteopetrosis v0.1 TNFRSF11A Catherine Snow gene: TNFRSF11A was added
gene: TNFRSF11A was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TNFRSF11A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: TNFRSF11A were set to Osteolysis, familial expansile 174810; {Paget disease of bone 2, early-onset} 602080; Osteopetrosis, autosomal recessive 7 612301
Osteopetrosis v0.1 TGFB1 Catherine Snow gene: TGFB1 was added
gene: TGFB1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TGFB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TGFB1 were set to Camurati-Engelmann disease 131300
Osteopetrosis v0.1 TCIRG1 Catherine Snow gene: TCIRG1 was added
gene: TCIRG1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TCIRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TCIRG1 were set to Osteopetrosis, autosomal recessive 1 259700
Osteopetrosis v0.1 SOST Catherine Snow gene: SOST was added
gene: SOST was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SOST was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SOST were set to Sclerosteosis 1 269500; Craniodiaphyseal dysplasia, autosomal dominant 122860; Van Buchem disease 239100
Osteopetrosis v0.1 SNX10 Catherine Snow gene: SNX10 was added
gene: SNX10 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8 615085
Osteopetrosis v0.1 RASGRP2 Catherine Snow gene: RASGRP2 was added
gene: RASGRP2 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: RASGRP2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RASGRP2 were set to ?Bleeding disorder, platelet-type, 18 615888
Osteopetrosis v0.1 PTH1R Catherine Snow gene: PTH1R was added
gene: PTH1R was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PTH1R was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: PTH1R were set to Chondrodysplasia, Blomstrand type 215045; Metaphyseal chondrodysplasia, Murk Jansen type 156400
Osteopetrosis v0.1 PLEKHM1 Catherine Snow gene: PLEKHM1 was added
gene: PLEKHM1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PLEKHM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: PLEKHM1 were set to ?Osteopetrosis, autosomal recessive 6 611497; Osteopetrosis, autosomal dominant 3 618107
Osteopetrosis v0.1 OSTM1 Catherine Snow gene: OSTM1 was added
gene: OSTM1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: OSTM1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OSTM1 were set to Osteopetrosis, autosomal recessive 5 259720
Osteopetrosis v0.1 LRP5 Catherine Snow gene: LRP5 was added
gene: LRP5 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: LRP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: LRP5 were set to Osteopetrosis, autosomal dominant 1 607634; Osteosclerosis 144750; Hyperostosis, endosteal 144750; [Bone mineral density variability 1] 601884; van Buchem disease, type 2 607636
Osteopetrosis v0.1 LEMD3 Catherine Snow gene: LEMD3 was added
gene: LEMD3 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: LEMD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: LEMD3 were set to Osteopoikilosis with or without melorheostosis 166700; Buschke-Ollendorff syndrome 166700
Osteopetrosis v0.1 IKBKG Catherine Snow gene: IKBKG was added
gene: IKBKG was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: IKBKG 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 gene: IKBKG were set to Ectodermal dysplasia and immunodeficiency 1 300291
Osteopetrosis v0.1 FERMT3 Catherine Snow gene: FERMT3 was added
gene: FERMT3 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FERMT3 were set to 18709451
Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III 612840
Osteopetrosis v0.1 FAM20C Catherine Snow gene: FAM20C was added
gene: FAM20C was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FAM20C was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAM20C were set to Raine syndrome 259775
Osteopetrosis v0.1 CTSK Catherine Snow gene: CTSK was added
gene: CTSK was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CTSK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CTSK were set to Pycnodysostosis 265800
Osteopetrosis v0.1 CLCN7 Catherine Snow gene: CLCN7 was added
gene: CLCN7 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CLCN7 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: CLCN7 were set to Osteopetrosis, autosomal recessive 4 611490; Osteopetrosis, autosomal dominant 2 166600
Osteopetrosis v0.1 CA2 Catherine Snow gene: CA2 was added
gene: CA2 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis 259730
Osteopetrosis v0.1 ANKH Catherine Snow gene: ANKH was added
gene: ANKH was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ANKH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ANKH were set to Chondrocalcinosis 2 118600; Craniometaphyseal dysplasia 123000
Osteopetrosis v0.1 AMER1 Catherine Snow gene: AMER1 was added
gene: AMER1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: AMER1 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 gene: AMER1 were set to Osteopathia striata with cranial sclerosis 300373
Thrombocythaemia v0.0 CALR Arina Puzriakova gene: CALR was added
gene: CALR was added to Thrombocythaemia. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: CALR was set to Unknown
Phenotypes for gene: CALR were set to Thrombocythemia, somatic, 187950
Thrombocythaemia v0.0 SH2B3 Arina Puzriakova gene: SH2B3 was added
gene: SH2B3 was added to Thrombocythaemia. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: SH2B3 was set to Unknown
Phenotypes for gene: SH2B3 were set to Thrombocythemia, somatic, 187950
Thrombocythaemia v0.0 JAK2 Arina Puzriakova gene: JAK2 was added
gene: JAK2 was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: JAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: JAK2 were set to Thrombocythemia 3, 614521
Thrombocythaemia v0.0 THPO Arina Puzriakova gene: THPO was added
gene: THPO was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: THPO was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: THPO were set to Thrombocythemia 1, 187950
Thrombocythaemia v0.0 MPL Arina Puzriakova gene: MPL was added
gene: MPL was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: MPL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MPL were set to Thrombocythemia 2, 601977
Thrombocythaemia v0.0 Arina Puzriakova Added panel Thrombocythaemia
Osteopetrosis v0.0 Catherine Snow Added Panel Osteopetrosis
Sudden unexplained death or survivors of a cardiac event v9.72 Ivone Leong Panel version has been signed off
Dilated and arrhythmogenic cardiomyopathy v1.5 Ivone Leong Panel version has been signed off
Progressive cardiac conduction disease v1.6 Ivone Leong Panel version has been signed off
Brugada syndrome and cardiac sodium channel disease v2.5 Ivone Leong Panel version has been signed off
Short QT syndrome v2.6 Ivone Leong Panel version has been signed off
Catecholaminergic polymorphic VT v2.6 Ivone Leong Panel version has been signed off
Hypertrophic cardiomyopathy v2.6 Ivone Leong Panel version has been signed off
Arrhythmogenic right ventricular cardiomyopathy v2.9 Ivone Leong Panel version has been signed off
Long QT syndrome v2.21 Ivone Leong Panel version has been signed off
Intellectual disability v3.262 SPOP Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to differences in additional clinical manifestations.
Intellectual disability v3.262 TASP1 Arina Puzriakova Tag for-review tag was added to gene: TASP1.
Intellectual disability v3.262 TASP1 Arina Puzriakova Classified gene: TASP1 as Amber List (moderate evidence)
Intellectual disability v3.262 TASP1 Arina Puzriakova Added comment: Comment on list classification: Sufficient cases for a GREEN rating at the next major review.

Associated with phenotype in OMIM, and a possible gene for Developmental delay, happy demeanor, distinctive facial features, and congenital anomalies in G2P.

Four unrelated patients with homozygous LOF variants in this gene all exhibited a consistent phenotype which included global developmental delay. All variants segregated with disease, but no functional studies of the variants or patient cells were not performed.
Intellectual disability v3.262 TASP1 Arina Puzriakova Gene: tasp1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.88 PSAT1 Sarah Leigh commented on gene: PSAT1: There is enough evidence for this gene to be rated GREEN at the next major review.
Fetal anomalies v1.88 PSAT1 Sarah Leigh Deleted their comment
Fetal anomalies v1.88 PSAT1 Sarah Leigh reviewed gene: PSAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.88 PSAT1 Sarah Leigh Tag for-review tag was added to gene: PSAT1.
Fetal anomalies v1.88 POLE Sarah Leigh Tag for-review tag was added to gene: POLE.
Neurodegenerative disorders, adult onset v2.12 ISCA-37478-Gain Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders, adult onset v2.12 ISCA-37468-Loss Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders, adult onset v2.12 ISCA-37404-Loss Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders, adult onset v2.12 ISCA-37478-Loss Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders, adult onset v2.12 Arina Puzriakova Panel version has been signed off
Intellectual disability v3.261 SPOP Arina Puzriakova Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1, 618828; Nabais Sa-de Vries syndrome, type 2, 618829
Neurodegenerative disorders, adult onset v2.10 Arina Puzriakova Panel version has been signed off
Cholestasis v1.22 Ivone Leong Panel version has been signed off
Dystonia, chorea or related movement disorder, childhood onset v1.49 Eleanor Williams Panel version has been signed off
Intellectual disability v3.260 SPOP Arina Puzriakova Tag for-review tag was added to gene: SPOP.
Intellectual disability v3.260 SPOP Arina Puzriakova Classified gene: SPOP as Amber List (moderate evidence)
Intellectual disability v3.260 SPOP Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.
Intellectual disability v3.260 SPOP Arina Puzriakova Gene: spop has been classified as Amber List (Moderate Evidence).
Skeletal muscle channelopathy v1.4 SLC2A1 Zornitza Stark reviewed gene: SLC2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 9, MIM# 601042; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal muscle channelopathy v1.4 SLC1A3 Zornitza Stark reviewed gene: SLC1A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Episodic ataxia, type 6, MIM# 612656; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal muscle channelopathy v1.4 PYGM Zornitza Stark reviewed gene: PYGM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: McArdle disease, 232600; Mode of inheritance: None
Skeletal muscle channelopathy v1.4 CACNA1A Zornitza Stark reviewed gene: CACNA1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Episodic ataxia, type 2, MIM# 108500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal muscle channelopathy v1.4 ATP1A2 Zornitza Stark reviewed gene: ATP1A2: Rating: RED; Mode of pathogenicity: None; Publications: 30423015; Phenotypes: Hypokalaemic periodic paralysis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain channelopathy v1.55 KCNMA1 Zornitza Stark gene: KCNMA1 was added
gene: KCNMA1 was added to Brain channelopathy. Sources: Expert list
Mode of inheritance for gene: KCNMA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNMA1 were set to 15937479; 26195193
Phenotypes for gene: KCNMA1 were set to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446
Review for gene: KCNMA1 was set to GREEN
gene: KCNMA1 was marked as current diagnostic
Added comment: Potassium channel gene which is associated with several phenotypes, including paroxysmal dyskinesia in at least three unrelated families.
Sources: Expert list
Brain channelopathy v1.55 KCNJ2 Zornitza Stark gene: KCNJ2 was added
gene: KCNJ2 was added to Brain channelopathy. Sources: Expert list
Mode of inheritance for gene: KCNJ2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ2 were set to 16217063; 16571646; 16419128; 17324964
Phenotypes for gene: KCNJ2 were set to Andersen syndrome, MIM# 170390
Review for gene: KCNJ2 was set to GREEN
Added comment: Multisystem channelopathy characterised by periodic paralysis as well as ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. > 10 families reported, well established gene-disease association.
Sources: Expert list
Fetal anomalies v1.88 TUBA8 Catherine Snow Classified gene: TUBA8 as Green List (high evidence)
Fetal anomalies v1.88 TUBA8 Catherine Snow Added comment: Comment on list classification: Change from Amber to Green, as requested by NHSE for signed-off panel.
Fetal anomalies v1.88 TUBA8 Catherine Snow Gene: tuba8 has been classified as Green List (High Evidence).
Fetal anomalies v1.87 SMG9 Catherine Snow Tag for-review tag was added to gene: SMG9.
Fetal anomalies v1.87 SMG9 Catherine Snow Classified gene: SMG9 as Amber List (moderate evidence)
Fetal anomalies v1.87 SMG9 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.87 SMG9 Catherine Snow Gene: smg9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.86 PSAT1 Catherine Snow Classified gene: PSAT1 as Amber List (moderate evidence)
Fetal anomalies v1.86 PSAT1 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.86 PSAT1 Catherine Snow Gene: psat1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.85 POLE Catherine Snow Classified gene: POLE as Amber List (moderate evidence)
Fetal anomalies v1.85 POLE Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.85 POLE Catherine Snow Gene: pole has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.84 GREB1L Catherine Snow Classified gene: GREB1L as Amber List (moderate evidence)
Fetal anomalies v1.84 GREB1L Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.84 GREB1L Catherine Snow Gene: greb1l has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Tag for-review tag was added to gene: EXOC3L2.
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Classified gene: EXOC3L2 as Amber List (moderate evidence)
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.82 CEP55 Catherine Snow Tag for-review tag was added to gene: CEP55.
Fetal anomalies v1.82 CEP55 Catherine Snow Classified gene: CEP55 as Amber List (moderate evidence)
Fetal anomalies v1.82 CEP55 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.82 CEP55 Catherine Snow Gene: cep55 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.81 ALG9 Catherine Snow Tag for-review tag was added to gene: ALG9.
Fetal anomalies v1.81 ALG9 Catherine Snow Classified gene: ALG9 as Amber List (moderate evidence)
Fetal anomalies v1.81 ALG9 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber as requested by NHSE for sign-off panel
Fetal anomalies v1.81 ALG9 Catherine Snow Gene: alg9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.80 TMEM94 Catherine Snow Classified gene: TMEM94 as Green List (high evidence)
Fetal anomalies v1.80 TMEM94 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.80 TMEM94 Catherine Snow Gene: tmem94 has been classified as Green List (High Evidence).
Fetal anomalies v1.79 GDF1 Catherine Snow Classified gene: GDF1 as Green List (high evidence)
Fetal anomalies v1.79 GDF1 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.79 GDF1 Catherine Snow Gene: gdf1 has been classified as Green List (High Evidence).
Fetal anomalies v1.78 COL3A1 Catherine Snow Classified gene: COL3A1 as Green List (high evidence)
Fetal anomalies v1.78 COL3A1 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.78 COL3A1 Catherine Snow Gene: col3a1 has been classified as Green List (High Evidence).
Fetal anomalies v1.77 CFAP53 Catherine Snow Classified gene: CFAP53 as Green List (high evidence)
Fetal anomalies v1.77 CFAP53 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.77 CFAP53 Catherine Snow Gene: cfap53 has been classified as Green List (High Evidence).
Fetal anomalies v1.76 CEP120 Catherine Snow Classified gene: CEP120 as Green List (high evidence)
Fetal anomalies v1.76 CEP120 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.76 CEP120 Catherine Snow Gene: cep120 has been classified as Green List (High Evidence).
Intellectual disability v3.259 POMK Arina Puzriakova Publications for gene: POMK were set to
Intellectual disability v3.258 POMK Arina Puzriakova Classified gene: POMK as Amber List (moderate evidence)
Intellectual disability v3.258 POMK Arina Puzriakova Added comment: Comment on list classification: Sufficient cases to support causation; however, ID is unlikely to be the main presenting feature of this phenotype - therefore, rating Amber on this panel.

POMK is rated Green on other relevant panels including Congenital muscular dystrophy, Hydrocephalus, and Arthrogryposis.
Intellectual disability v3.258 POMK Arina Puzriakova Gene: pomk has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.75 ACVR2B Catherine Snow Classified gene: ACVR2B as Green List (high evidence)
Fetal anomalies v1.75 ACVR2B Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.75 ACVR2B Catherine Snow Gene: acvr2b has been classified as Green List (High Evidence).
Bilateral congenital or childhood onset cataracts v2.9 PISD Arina Puzriakova changed review comment from: Comment on list classification: Rating Red, as cataracts (congenital) only reported in a single family with two affects sibs - additional cases required to ascertain the contribution of PISD variants to this phenotype.; to: Comment on list classification: Rating Red, as cataracts (congenital) only reported in a single family with two affected sibs - additional cases required to ascertain the contribution of PISD variants to this phenotype.
Skeletal dysplasia v2.13 PISD Arina Puzriakova Classified gene: PISD as Amber List (moderate evidence)
Skeletal dysplasia v2.13 PISD Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN on the next major review - at least five unrelated families (three with the same founder variant) presenting skeletal dysplasia associated with biallelic variants in this gene.
Skeletal dysplasia v2.13 PISD Arina Puzriakova Gene: pisd has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.12 PISD Arina Puzriakova gene: PISD was added
gene: PISD was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: PISD.
Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PISD were set to 31263216; 30858161; 30488656; 3561949
Phenotypes for gene: PISD were set to Liberfarb syndrome, 618889
Review for gene: PISD was set to GREEN
Added comment: Associated with Liberfarb syndrome in OMIM, but not in G2P.

PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by skeletal dysplasia, short stature, early-onset retinal degeneration, developmental delay, microcephaly, and hearing loss. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals.

PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene.

PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts.
Sources: Literature
Intellectual disability v3.257 PISD Arina Puzriakova Classified gene: PISD as Amber List (moderate evidence)
Intellectual disability v3.257 PISD Arina Puzriakova Added comment: Comment on list classification: Four families presenting a DD/ID phenotype, but three share the same founder variant - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.257 PISD Arina Puzriakova Gene: pisd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.256 PISD Arina Puzriakova Tag watchlist tag was added to gene: PISD.
Intellectual disability v3.256 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656, 3561949; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.9 PISD Arina Puzriakova Publications for gene: PISD were set to 31263216; 30858161
Bilateral congenital or childhood onset cataracts v2.8 PISD Arina Puzriakova Phenotypes for gene: PISD were changed from Intellectual disability; cataracts; retinal degeneration; microcephaly; deafness; short stature; white matter abnormalities to Liberfarb syndrome, 618889
Bilateral congenital or childhood onset cataracts v2.7 PISD Arina Puzriakova Classified gene: PISD as Red List (low evidence)
Bilateral congenital or childhood onset cataracts v2.7 PISD Arina Puzriakova Added comment: Comment on list classification: Rating Red, as cataracts (congenital) only reported in a single family with two affects sibs - additional cases required to ascertain the contribution of PISD variants to this phenotype.
Bilateral congenital or childhood onset cataracts v2.7 PISD Arina Puzriakova Gene: pisd has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v2.6 PISD Arina Puzriakova edited their review of gene: PISD: Changed publications: 31263216, 30858161, 30488656, 3561949
Bilateral congenital or childhood onset cataracts v2.6 PISD Arina Puzriakova changed review comment from: PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by early-onset retinal degeneration, skeletal dysplasia, short stature, developmental delay, microcephaly, and hearing loss. There was a concern for bilateral cataracts in one patient (patient 3), but a formal ophthalmological evaluation could not be performed. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals.

PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene.

PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts.; to: Associated with Liberfarb syndrome in OMIM, but not in G2P.

PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by early-onset retinal degeneration, skeletal dysplasia, short stature, developmental delay, microcephaly, and hearing loss. There was a concern for bilateral cataracts in one patient (patient 3), but a formal ophthalmological evaluation could not be performed. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals.

PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene.

PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts.
Bilateral congenital or childhood onset cataracts v2.6 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.256 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Renal ciliopathies v1.28 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Renal ciliopathies v1.27 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Red List (low evidence)
Renal ciliopathies v1.27 PIBF1 Arina Puzriakova Added comment: Comment on list classification: Keeping rating Red, as renal manifestation only reported in a single patient - awaiting further publications/clinical evidence to ascertain the contribution of variants in PIBF1 to this phenotype.
Renal ciliopathies v1.27 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Red List (Low Evidence).
Renal ciliopathies v1.26 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: ; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurological ciliopathies v1.9 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Neurological ciliopathies v1.9 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Neurological ciliopathies v1.8 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Amber List (moderate evidence)
Neurological ciliopathies v1.8 PIBF1 Arina Puzriakova Added comment: Comment on list classification: With the addition of the two recent reports, there are now at least 7 total families (4 with same founder variant) with Joubert syndrome associated with biallelic variants in this gene.
Neurological ciliopathies v1.8 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.7 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.8 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Red List (low evidence)
Ophthalmological ciliopathies v1.8 PIBF1 Arina Puzriakova Added comment: Comment on list classification: Keeping rating Red as ophthalmological phenotype has been absent from all cases reported to date.
Ophthalmological ciliopathies v1.8 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Red List (Low Evidence).
Ophthalmological ciliopathies v1.7 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Ophthalmological ciliopathies v1.6 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: ; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: None
Hereditary Erythrocytosis v1.11 Sarah Leigh List of related panels changed from to R405
Panel types changed to Rare Disease 100K; GMS signed-off
Long QT syndrome v2.17 TRDN Ivone Leong Classified gene: TRDN as Amber List (moderate evidence)
Long QT syndrome v2.17 TRDN Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Amber at the request of NHS England following discussion at a Rare Disease workshop.
Long QT syndrome v2.17 TRDN Ivone Leong Gene: trdn has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Classified gene: BPGM as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in 3 unrelated cases, although two of the cases are biallelic (PMID 25015942, 15054810), one case appears to monoallelic (PMID 25015942).
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Gene: bpgm has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.9 BPGM Sarah Leigh Added comment: Comment on phenotypes: Erythrocytosis due to bisphosphoglycerate mutase deficiency
Hereditary Erythrocytosis v1.9 BPGM Sarah Leigh Phenotypes for gene: BPGM were changed from Erythrocytosis due to bisphosphoglycerate mutase deficiency to Erythrocytosis, familial, 8 222800
Long QT syndrome v2.16 TRDN Ivone Leong Tag for-review tag was added to gene: TRDN.
Neurodegenerative disorders, adult onset v2.8 ISCA-37478-Loss Arina Puzriakova Classified Region: ISCA-37478-Loss as No list
Neurodegenerative disorders, adult onset v2.8 ISCA-37478-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders, adult onset v2.8 ISCA-37478-Loss Arina Puzriakova Region: isca-37478-loss has been removed from the panel.
Neurodegenerative disorders, adult onset v2.7 ISCA-37478-Gain Arina Puzriakova Classified Region: ISCA-37478-Gain as No list
Neurodegenerative disorders, adult onset v2.7 ISCA-37478-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders, adult onset v2.7 ISCA-37478-Gain Arina Puzriakova Region: isca-37478-gain has been removed from the panel.
Neurodegenerative disorders, adult onset v2.6 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Neurodegenerative disorders, adult onset v2.6 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders, adult onset v2.6 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Neurodegenerative disorders, adult onset v2.5 ISCA-37468-Loss Arina Puzriakova Classified Region: ISCA-37468-Loss as No list
Neurodegenerative disorders, adult onset v2.5 ISCA-37468-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders, adult onset v2.5 ISCA-37468-Loss Arina Puzriakova Region: isca-37468-loss has been removed from the panel.
Palmoplantar keratodermas v1.3 ARSE Zornitza Stark reviewed gene: ARSE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked recessive, MIM# 302950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Palmoplantar keratodermas v1.3 CASP14 Zornitza Stark reviewed gene: CASP14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 CLDN1 Zornitza Stark reviewed gene: CLDN1: Rating: RED; Mode of pathogenicity: None; Publications: 15521008; Phenotypes: Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (MIM#607626); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 MVK Zornitza Stark reviewed gene: MVK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porokeratosis 3, multiple types, MIM# 175900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratodermas v1.3 PEX7 Zornitza Stark reviewed gene: PEX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Peroxisome biogenesis disorder 9B (AR), Rhizomelic chondrodysplasia punctata, type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 PHYH Zornitza Stark reviewed gene: PHYH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Refsum disease (MIM#266500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 SLC27A4 Zornitza Stark reviewed gene: SLC27A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis prematurity syndrome (MIM#608649); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 ST14 Zornitza Stark reviewed gene: ST14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis, congenital, autosomal recessive 11 (MIM#602400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 STK11 Zornitza Stark reviewed gene: STK11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Peutz-Jeghers syndrome (MIM#175200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.45 COL6A3 Eleanor Williams Tag for-review tag was added to gene: COL6A3.
Dystonia, chorea or related movement disorder, childhood onset v1.45 COL6A3 Eleanor Williams reviewed gene: COL6A3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Rare multisystem ciliopathy disorders v1.129 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Rare multisystem ciliopathy disorders v1.128 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.128 PIBF1 Arina Puzriakova Added comment: Comment on list classification: With the addition of the two recent reports, there are now at least 7 total families (4 with same founder variant) with Joubert syndrome associated with biallelic variants in this gene.
Rare multisystem ciliopathy disorders v1.128 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.127 PIBF1 Arina Puzriakova Tag for-review was removed from gene: PIBF1.
Rare multisystem ciliopathy disorders v1.127 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Rare multisystem ciliopathy disorders v1.127 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.8 JAK2 Sarah Leigh changed review comment from: GMS Expert list Green
Sources: Expert list, NHS GMS; to: GMS Expert review Green
Sources: Expert review, NHS GMS
Hereditary Erythrocytosis v1.8 SH2B3 Sarah Leigh changed review comment from: GMS Expert list Green
Sources: NHS GMS, Expert list; to: GMS Expert review Green
Sources: NHS GMS, Expert review
Hereditary Erythrocytosis v1.8 SH2B3 Sarah Leigh Classified gene: SH2B3 as Green List (high evidence)
Hereditary Erythrocytosis v1.8 SH2B3 Sarah Leigh Gene: sh2b3 has been classified as Green List (High Evidence).
Hereditary Erythrocytosis v1.7 SH2B3 Sarah Leigh gene: SH2B3 was added
gene: SH2B3 was added to Hereditary Erythrocytosis. Sources: NHS GMS,Expert list
somatic tags were added to gene: SH2B3.
Mode of inheritance for gene: SH2B3 was set to Unknown
Phenotypes for gene: SH2B3 were set to Erythrocytosis, somatic 133100
Review for gene: SH2B3 was set to GREEN
Added comment: GMS Expert list Green
Sources: NHS GMS, Expert list
Hereditary Erythrocytosis v1.6 JAK2 Sarah Leigh Classified gene: JAK2 as Green List (high evidence)
Hereditary Erythrocytosis v1.6 JAK2 Sarah Leigh Gene: jak2 has been classified as Green List (High Evidence).
Hereditary Erythrocytosis v1.5 JAK2 Sarah Leigh gene: JAK2 was added
gene: JAK2 was added to Hereditary Erythrocytosis. Sources: Expert list,NHS GMS
somatic tags were added to gene: JAK2.
Mode of inheritance for gene: JAK2 was set to Unknown
Phenotypes for gene: JAK2 were set to Erythrocytosis, somatic 133100
Review for gene: JAK2 was set to GREEN
Added comment: GMS Expert list Green
Sources: Expert list, NHS GMS
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TY Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TW Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TV Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TT Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TS2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TS1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TR Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TQ Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TP Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TN Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TM Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TL2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TL1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TI Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TH Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TG Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TF Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TE Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TD Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TA Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-RNR2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-RNR1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND4L Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-CYB Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-CO2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-CO1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ATP8 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TK Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TC Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND6 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND5 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND4 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND3 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ND1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-CO3 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-ATP6 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TY Eleanor Williams Classified gene: MT-TY as No list
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TY Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.45 MT-TY Eleanor Williams Gene: mt-ty has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.44 MT-TW Eleanor Williams Classified gene: MT-TW as No list
Dystonia, chorea or related movement disorder, childhood onset v1.44 MT-TW Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.44 MT-TW Eleanor Williams Gene: mt-tw has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.43 MT-TV Eleanor Williams Classified gene: MT-TV as No list
Dystonia, chorea or related movement disorder, childhood onset v1.43 MT-TV Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.43 MT-TV Eleanor Williams Gene: mt-tv has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.42 MT-TT Eleanor Williams Classified gene: MT-TT as No list
Dystonia, chorea or related movement disorder, childhood onset v1.42 MT-TT Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.42 MT-TT Eleanor Williams Gene: mt-tt has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.41 MT-TS2 Eleanor Williams Classified gene: MT-TS2 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.41 MT-TS2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.41 MT-TS2 Eleanor Williams Gene: mt-ts2 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.40 MT-TS1 Eleanor Williams Classified gene: MT-TS1 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.40 MT-TS1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.40 MT-TS1 Eleanor Williams Gene: mt-ts1 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.39 MT-TR Eleanor Williams Classified gene: MT-TR as No list
Dystonia, chorea or related movement disorder, childhood onset v1.39 MT-TR Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.39 MT-TR Eleanor Williams Gene: mt-tr has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.38 MT-TQ Eleanor Williams Classified gene: MT-TQ as No list
Dystonia, chorea or related movement disorder, childhood onset v1.38 MT-TQ Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.38 MT-TQ Eleanor Williams Gene: mt-tq has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.37 MT-TP Eleanor Williams Classified gene: MT-TP as No list
Dystonia, chorea or related movement disorder, childhood onset v1.37 MT-TP Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.37 MT-TP Eleanor Williams Gene: mt-tp has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.36 MT-TN Eleanor Williams Classified gene: MT-TN as No list
Dystonia, chorea or related movement disorder, childhood onset v1.36 MT-TN Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.36 MT-TN Eleanor Williams Gene: mt-tn has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.35 MT-TM Eleanor Williams Classified gene: MT-TM as No list
Dystonia, chorea or related movement disorder, childhood onset v1.35 MT-TM Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.35 MT-TM Eleanor Williams Gene: mt-tm has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.34 MT-TL2 Eleanor Williams Classified gene: MT-TL2 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.34 MT-TL2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.34 MT-TL2 Eleanor Williams Gene: mt-tl2 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.33 MT-TL1 Eleanor Williams Classified gene: MT-TL1 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.33 MT-TL1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.33 MT-TL1 Eleanor Williams Gene: mt-tl1 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.32 MT-TI Eleanor Williams Classified gene: MT-TI as No list
Dystonia, chorea or related movement disorder, childhood onset v1.32 MT-TI Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.32 MT-TI Eleanor Williams Gene: mt-ti has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.31 MT-TH Eleanor Williams Classified gene: MT-TH as No list
Dystonia, chorea or related movement disorder, childhood onset v1.31 MT-TH Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.31 MT-TH Eleanor Williams Gene: mt-th has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.30 MT-TG Eleanor Williams Classified gene: MT-TG as No list
Dystonia, chorea or related movement disorder, childhood onset v1.30 MT-TG Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.30 MT-TG Eleanor Williams Gene: mt-tg has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.29 MT-TF Eleanor Williams Classified gene: MT-TF as No list
Dystonia, chorea or related movement disorder, childhood onset v1.29 MT-TF Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.29 MT-TF Eleanor Williams Gene: mt-tf has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.28 MT-TE Eleanor Williams Classified gene: MT-TE as No list
Dystonia, chorea or related movement disorder, childhood onset v1.28 MT-TE Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.28 MT-TE Eleanor Williams Gene: mt-te has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.27 MT-TD Eleanor Williams Classified gene: MT-TD as No list
Dystonia, chorea or related movement disorder, childhood onset v1.27 MT-TD Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.27 MT-TD Eleanor Williams Gene: mt-td has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.26 MT-TA Eleanor Williams Classified gene: MT-TA as No list
Dystonia, chorea or related movement disorder, childhood onset v1.26 MT-TA Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.26 MT-TA Eleanor Williams Gene: mt-ta has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.25 MT-RNR2 Eleanor Williams Classified gene: MT-RNR2 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.25 MT-RNR2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.25 MT-RNR2 Eleanor Williams Gene: mt-rnr2 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.24 MT-RNR1 Eleanor Williams Classified gene: MT-RNR1 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.24 MT-RNR1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.24 MT-RNR1 Eleanor Williams Gene: mt-rnr1 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.23 MT-ND4L Eleanor Williams Classified gene: MT-ND4L as No list
Dystonia, chorea or related movement disorder, childhood onset v1.23 MT-ND4L Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.23 MT-ND4L Eleanor Williams Gene: mt-nd4l has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.22 MT-ND2 Eleanor Williams Classified gene: MT-ND2 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.22 MT-ND2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.22 MT-ND2 Eleanor Williams Gene: mt-nd2 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.21 MT-CYB Eleanor Williams Classified gene: MT-CYB as No list
Dystonia, chorea or related movement disorder, childhood onset v1.21 MT-CYB Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.21 MT-CYB Eleanor Williams Gene: mt-cyb has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.20 MT-CO2 Eleanor Williams Classified gene: MT-CO2 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.20 MT-CO2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.20 MT-CO2 Eleanor Williams Gene: mt-co2 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.19 MT-CO1 Eleanor Williams Classified gene: MT-CO1 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.19 MT-CO1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.19 MT-CO1 Eleanor Williams Gene: mt-co1 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.18 MT-ATP8 Eleanor Williams Classified gene: MT-ATP8 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.18 MT-ATP8 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.18 MT-ATP8 Eleanor Williams Gene: mt-atp8 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.17 MT-TK Eleanor Williams Classified gene: MT-TK as No list
Dystonia, chorea or related movement disorder, childhood onset v1.17 MT-TK Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.17 MT-TK Eleanor Williams Gene: mt-tk has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.16 MT-TC Eleanor Williams Classified gene: MT-TC as No list
Dystonia, chorea or related movement disorder, childhood onset v1.16 MT-TC Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.16 MT-TC Eleanor Williams Gene: mt-tc has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.15 MT-ND6 Eleanor Williams Classified gene: MT-ND6 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.15 MT-ND6 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.15 MT-ND6 Eleanor Williams Gene: mt-nd6 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.14 MT-ND5 Eleanor Williams Classified gene: MT-ND5 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.14 MT-ND5 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.14 MT-ND5 Eleanor Williams Gene: mt-nd5 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.13 MT-ND4 Eleanor Williams Classified gene: MT-ND4 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.13 MT-ND4 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.13 MT-ND4 Eleanor Williams Gene: mt-nd4 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.12 MT-ND3 Eleanor Williams Classified gene: MT-ND3 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.12 MT-ND3 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.12 MT-ND3 Eleanor Williams Gene: mt-nd3 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.11 MT-ND1 Eleanor Williams Classified gene: MT-ND1 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.11 MT-ND1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.11 MT-ND1 Eleanor Williams Gene: mt-nd1 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.10 MT-CO3 Eleanor Williams Classified gene: MT-CO3 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.10 MT-CO3 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Dystonia, chorea or related movement disorder, childhood onset v1.10 MT-CO3 Eleanor Williams Gene: mt-co3 has been removed from the panel.
Dystonia, chorea or related movement disorder, childhood onset v1.9 MT-ATP6 Eleanor Williams Classified gene: MT-ATP6 as No list
Dystonia, chorea or related movement disorder, childhood onset v1.9 MT-ATP6 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Dystonia, chorea or related movement disorder, childhood onset v1.9 MT-ATP6 Eleanor Williams Gene: mt-atp6 has been removed from the panel.
Hereditary Erythrocytosis v1.4 EPO Sarah Leigh Added comment: Comment on mode of inheritance: Biallelic variants have been associated with ?Diamond-Blackfan anemia-like 617911
Hereditary Erythrocytosis v1.4 EPO Sarah Leigh Mode of inheritance for gene: EPO was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary Erythrocytosis v1.3 EPO Sarah Leigh Phenotypes for gene: EPO were changed from Hereditary Erythrocytosis to Erythrocytosis, familial, 5 617907
Hereditary Erythrocytosis v1.2 EPO Sarah Leigh Classified gene: EPO as Green List (high evidence)
Hereditary Erythrocytosis v1.2 EPO Sarah Leigh Added comment: Comment on list classification: GMS, Expert list Green
Hereditary Erythrocytosis v1.2 EPO Sarah Leigh Gene: epo has been classified as Green List (High Evidence).
Sudden unexplained death or survivors of a cardiac event v9.48 Ivone Leong List of related panels changed from Molecular autopsy; R138 to Molecular autopsy; R138; R408
Cholestasis v1.19 CC2D2A Ivone Leong Classified gene: CC2D2A as No list
Cholestasis v1.19 CC2D2A Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).
Cholestasis v1.19 CC2D2A Ivone Leong Gene: cc2d2a has been removed from the panel.
Cholestasis v1.18 TMEM67 Ivone Leong Classified gene: TMEM67 as No list
Cholestasis v1.18 TMEM67 Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).
Cholestasis v1.18 TMEM67 Ivone Leong Gene: tmem67 has been removed from the panel.
Cholestasis v1.17 TMEM67 Ivone Leong Tag for-review was removed from gene: TMEM67.
Cholestasis v1.17 RPGRIP1L Ivone Leong Classified gene: RPGRIP1L as No list
Cholestasis v1.17 RPGRIP1L Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).
Cholestasis v1.17 RPGRIP1L Ivone Leong Gene: rpgrip1l has been removed from the panel.
Intellectual disability v3.256 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Amber List (moderate evidence)
Intellectual disability v3.256 PIBF1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 7 families (4 with same founder variant) with Joubert syndrome, which is associated with global DD/ID.
Intellectual disability v3.256 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.255 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.255 TAF1C Konstantinos Varvagiannis gene: TAF1C was added
gene: TAF1C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Penetrance for gene: TAF1C were set to Complete
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants.

Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual).

Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1).

The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele.

TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit.

RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs).

A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data).

The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.255 ZMPSTE24 Arina Puzriakova commented on gene: ZMPSTE24
Intellectual disability v3.255 ZIC3 Arina Puzriakova commented on gene: ZIC3
Intellectual disability v3.255 XPC Arina Puzriakova commented on gene: XPC
Intellectual disability v3.255 WRAP53 Arina Puzriakova commented on gene: WRAP53
Intellectual disability v3.255 WNT7A Arina Puzriakova commented on gene: WNT7A
Intellectual disability v3.255 WNT3 Arina Puzriakova commented on gene: WNT3
Intellectual disability v3.255 WNT10B Arina Puzriakova commented on gene: WNT10B
Intellectual disability v3.255 WDR35 Arina Puzriakova commented on gene: WDR35
Intellectual disability v3.254 WDR34 Arina Puzriakova commented on gene: WDR34
Intellectual disability v3.254 WDR19 Arina Puzriakova commented on gene: WDR19
Intellectual disability v3.254 VSX2 Arina Puzriakova commented on gene: VSX2
Intellectual disability v3.254 UVSSA Arina Puzriakova commented on gene: UVSSA
Intellectual disability v3.254 USB1 Arina Puzriakova commented on gene: USB1
Intellectual disability v3.254 UROS Arina Puzriakova commented on gene: UROS
Intellectual disability v3.254 UGT1A1 Arina Puzriakova commented on gene: UGT1A1
Intellectual disability v3.254 TYRP1 Arina Puzriakova commented on gene: TYRP1
Intellectual disability v3.254 TYR Arina Puzriakova commented on gene: TYR
Intellectual disability v3.254 TXNL4A Arina Puzriakova commented on gene: TXNL4A
Intellectual disability v3.254 TUBA8 Arina Puzriakova commented on gene: TUBA8
Intellectual disability v3.254 TSHR Arina Puzriakova commented on gene: TSHR
Intellectual disability v3.254 TRPV4 Arina Puzriakova commented on gene: TRPV4
Intellectual disability v3.254 TRPS1 Arina Puzriakova commented on gene: TRPS1
Intellectual disability v3.254 TRPM1 Arina Puzriakova commented on gene: TRPM1
Intellectual disability v3.254 TRIP11 Arina Puzriakova commented on gene: TRIP11
Intellectual disability v3.254 TRAPPC2 Arina Puzriakova commented on gene: TRAPPC2
Intellectual disability v3.254 TP63 Arina Puzriakova commented on gene: TP63
Intellectual disability v3.254 TMPRSS6 Arina Puzriakova commented on gene: TMPRSS6
Intellectual disability v3.254 TMEM126B Arina Puzriakova commented on gene: TMEM126B
Intellectual disability v3.254 TGFB3 Arina Puzriakova commented on gene: TGFB3
Intellectual disability v3.254 TGFB2 Arina Puzriakova commented on gene: TGFB2
Intellectual disability v3.254 TEK Arina Puzriakova commented on gene: TEK
Intellectual disability v3.254 TCF12 Arina Puzriakova commented on gene: TCF12
Intellectual disability v3.254 TBXAS1 Arina Puzriakova commented on gene: TBXAS1
Intellectual disability v3.254 TBX5 Arina Puzriakova commented on gene: TBX5
Intellectual disability v3.254 TBX4 Arina Puzriakova commented on gene: TBX4
Intellectual disability v3.254 TBX3 Arina Puzriakova commented on gene: TBX3
Intellectual disability v3.254 TBX22 Arina Puzriakova commented on gene: TBX22
Intellectual disability v3.254 TBX20 Arina Puzriakova commented on gene: TBX20
Intellectual disability v3.254 TBX15 Arina Puzriakova commented on gene: TBX15
Intellectual disability v3.254 TAB2 Arina Puzriakova commented on gene: TAB2
Intellectual disability v3.254 STS Arina Puzriakova commented on gene: STS
Intellectual disability v3.254 STAT1 Arina Puzriakova commented on gene: STAT1
Intellectual disability v3.254 STAR Arina Puzriakova commented on gene: STAR
Intellectual disability v3.254 SRY Arina Puzriakova commented on gene: SRY
Intellectual disability v3.254 SPEG Arina Puzriakova commented on gene: SPEG
Intellectual disability v3.254 SPAG1 Arina Puzriakova commented on gene: SPAG1
Intellectual disability v3.254 SOX17 Arina Puzriakova commented on gene: SOX17
Intellectual disability v3.254 SMCHD1 Arina Puzriakova commented on gene: SMCHD1
Intellectual disability v3.254 SCN4A Arina Puzriakova commented on gene: SCN4A
Intellectual disability v3.254 RUNX2 Arina Puzriakova commented on gene: RUNX2
Intellectual disability v3.254 RSPO4 Arina Puzriakova commented on gene: RSPO4
Intellectual disability v3.254 RSPH3 Arina Puzriakova commented on gene: RSPH3
Intellectual disability v3.254 RSPH1 Arina Puzriakova commented on gene: RSPH1
Intellectual disability v3.254 RPS19 Arina Puzriakova commented on gene: RPS19
Intellectual disability v3.254 RPGRIP1 Arina Puzriakova commented on gene: RPGRIP1
Intellectual disability v3.254 RPE65 Arina Puzriakova commented on gene: RPE65
Intellectual disability v3.254 ROBO3 Arina Puzriakova commented on gene: ROBO3
Intellectual disability v3.254 RETREG1 Arina Puzriakova commented on gene: RETREG1
Intellectual disability v3.253 RASA1 Arina Puzriakova commented on gene: RASA1
Intellectual disability v3.253 PGM1 Arina Puzriakova commented on gene: PGM1
Intellectual disability v3.253 PDE6G Arina Puzriakova commented on gene: PDE6G
Intellectual disability v3.253 PAX9 Arina Puzriakova commented on gene: PAX9
Intellectual disability v3.253 PAX3 Arina Puzriakova commented on gene: PAX3
Intellectual disability v3.253 PAPSS2 Arina Puzriakova commented on gene: PAPSS2
Intellectual disability v3.253 OTULIN Arina Puzriakova commented on gene: OTULIN
Intellectual disability v3.253 OTOGL Arina Puzriakova commented on gene: OTOGL
Intellectual disability v3.253 ORC6 Arina Puzriakova commented on gene: ORC6
Intellectual disability v3.253 NRXN2 Arina Puzriakova commented on gene: NRXN2
Intellectual disability v3.253 NR5A1 Arina Puzriakova commented on gene: NR5A1
Intellectual disability v3.253 NR2F2 Arina Puzriakova commented on gene: NR2F2
Intellectual disability v3.253 NPR2 Arina Puzriakova commented on gene: NPR2
Intellectual disability v3.253 NPHS1 Arina Puzriakova commented on gene: NPHS1
Intellectual disability v3.253 NPHP4 Arina Puzriakova commented on gene: NPHP4
Intellectual disability v3.253 NOTCH2 Arina Puzriakova commented on gene: NOTCH2
Intellectual disability v3.253 NOG Arina Puzriakova commented on gene: NOG
Intellectual disability v3.253 NODAL Arina Puzriakova commented on gene: NODAL
Intellectual disability v3.253 NMNAT1 Arina Puzriakova commented on gene: NMNAT1
Intellectual disability v3.253 NKX3-2 Arina Puzriakova commented on gene: NKX3-2
Intellectual disability v3.253 NEK1 Arina Puzriakova commented on gene: NEK1
Intellectual disability v3.253 MYO5B Arina Puzriakova commented on gene: MYO5B
Intellectual disability v3.253 MYH9 Arina Puzriakova commented on gene: MYH9
Intellectual disability v3.253 MYH8 Arina Puzriakova commented on gene: MYH8
Intellectual disability v3.253 MYH6 Arina Puzriakova commented on gene: MYH6
Intellectual disability v3.253 MSX2 Arina Puzriakova commented on gene: MSX2
Intellectual disability v3.253 MSX1 Arina Puzriakova commented on gene: MSX1
Intellectual disability v3.253 MNX1 Arina Puzriakova commented on gene: MNX1
Intellectual disability v3.253 MMP13 Arina Puzriakova commented on gene: MMP13
Intellectual disability v3.253 MFRP Arina Puzriakova commented on gene: MFRP
Intellectual disability v3.253 MESP2 Arina Puzriakova commented on gene: MESP2
Intellectual disability v3.253 MC2R Arina Puzriakova commented on gene: MC2R
Intellectual disability v3.253 MATN3 Arina Puzriakova commented on gene: MATN3
Intellectual disability v3.253 MAPK10 Arina Puzriakova commented on gene: MAPK10
Intellectual disability v3.253 MAP3K1 Arina Puzriakova commented on gene: MAP3K1
Intellectual disability v3.253 LTBP3 Arina Puzriakova commented on gene: LTBP3
Intellectual disability v3.253 LTBP2 Arina Puzriakova commented on gene: LTBP2
Intellectual disability v3.253 LRRC6 Arina Puzriakova commented on gene: LRRC6
Intellectual disability v3.253 LRP4 Arina Puzriakova commented on gene: LRP4
Intellectual disability v3.253 LMX1B Arina Puzriakova commented on gene: LMX1B
Intellectual disability v3.253 LMNA Arina Puzriakova commented on gene: LMNA
Intellectual disability v3.253 LHX4 Arina Puzriakova commented on gene: LHX4
Intellectual disability v3.253 LHX3 Arina Puzriakova commented on gene: LHX3
Intellectual disability v3.253 LFNG Arina Puzriakova commented on gene: LFNG
Intellectual disability v3.253 LEMD3 Arina Puzriakova commented on gene: LEMD3
Intellectual disability v3.253 LDB3 Arina Puzriakova commented on gene: LDB3
Intellectual disability v3.253 KLHL40 Arina Puzriakova commented on gene: KLHL40
Intellectual disability v3.253 KLF1 Arina Puzriakova commented on gene: KLF1
Intellectual disability v3.253 KIT Arina Puzriakova commented on gene: KIT
Intellectual disability v3.253 KIRREL3 Arina Puzriakova commented on gene: KIRREL3
Intellectual disability v3.252 KIF22 Arina Puzriakova commented on gene: KIF22
Intellectual disability v3.252 KCTD1 Arina Puzriakova commented on gene: KCTD1
Intellectual disability v3.252 KCNQ1 Arina Puzriakova commented on gene: KCNQ1
Intellectual disability v3.252 KCND3 Arina Puzriakova commented on gene: KCND3
Intellectual disability v3.252 KBTBD13 Arina Puzriakova commented on gene: KBTBD13
Intellectual disability v3.252 JAK3 Arina Puzriakova commented on gene: JAK3
Intellectual disability v3.252 JAGN1 Arina Puzriakova commented on gene: JAGN1
Intellectual disability v3.252 JAG1 Arina Puzriakova commented on gene: JAG1
Intellectual disability v3.252 IRF6 Arina Puzriakova commented on gene: IRF6
Intellectual disability v3.252 INPPL1 Arina Puzriakova commented on gene: INPPL1
Intellectual disability v3.252 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Intellectual disability v3.252 IL11RA Arina Puzriakova commented on gene: IL11RA
Intellectual disability v3.252 IHH Arina Puzriakova commented on gene: IHH
Intellectual disability v3.252 IGF2 Arina Puzriakova commented on gene: IGF2
Intellectual disability v3.252 IFT80 Arina Puzriakova commented on gene: IFT80
Intellectual disability v3.252 IFT122 Arina Puzriakova commented on gene: IFT122
Intellectual disability v3.252 IFITM5 Arina Puzriakova commented on gene: IFITM5
Intellectual disability v3.252 HYDIN Arina Puzriakova commented on gene: HYDIN
Intellectual disability v3.252 HYAL1 Arina Puzriakova commented on gene: HYAL1
Intellectual disability v3.252 HSF4 Arina Puzriakova commented on gene: HSF4
Intellectual disability v3.252 HSD3B7 Arina Puzriakova commented on gene: HSD3B7
Intellectual disability v3.252 HR Arina Puzriakova commented on gene: HR
Intellectual disability v3.252 HPSE2 Arina Puzriakova commented on gene: HPSE2
Intellectual disability v3.252 HPS1 Arina Puzriakova commented on gene: HPS1
Intellectual disability v3.252 HPGD Arina Puzriakova commented on gene: HPGD
Intellectual disability v3.252 HOXD13 Arina Puzriakova commented on gene: HOXD13
Intellectual disability v3.252 HOXC13 Arina Puzriakova commented on gene: HOXC13
Intellectual disability v3.252 HOXA13 Arina Puzriakova commented on gene: HOXA13
Intellectual disability v3.252 HNF4A Arina Puzriakova commented on gene: HNF4A
Intellectual disability v3.252 HMGCS2 Arina Puzriakova commented on gene: HMGCS2
Intellectual disability v3.252 GUCY2C Arina Puzriakova commented on gene: GUCY2C
Intellectual disability v3.252 GRM6 Arina Puzriakova commented on gene: GRM6
Intellectual disability v3.252 GRHL3 Arina Puzriakova commented on gene: GRHL3
Intellectual disability v3.252 GPR179 Arina Puzriakova commented on gene: GPR179
Intellectual disability v3.252 GNAI3 Arina Puzriakova commented on gene: GNAI3
Intellectual disability v3.252 GLMN Arina Puzriakova commented on gene: GLMN
Intellectual disability v3.252 GLE1 Arina Puzriakova commented on gene: GLE1
Intellectual disability v3.252 GJB1 Arina Puzriakova commented on gene: GJB1
Intellectual disability v3.252 GJA8 Arina Puzriakova commented on gene: GJA8
Intellectual disability v3.252 GJA3 Arina Puzriakova commented on gene: GJA3
Intellectual disability v3.252 GJA1 Arina Puzriakova commented on gene: GJA1
Intellectual disability v3.252 GHR Arina Puzriakova commented on gene: GHR
Intellectual disability v3.252 GDF6 Arina Puzriakova commented on gene: GDF6
Intellectual disability v3.252 GDF5 Arina Puzriakova commented on gene: GDF5
Intellectual disability v3.252 GBA2 Arina Puzriakova commented on gene: GBA2
Intellectual disability v3.252 GATA4 Arina Puzriakova commented on gene: GATA4
Intellectual disability v3.252 GATA2 Arina Puzriakova commented on gene: GATA2
Intellectual disability v3.252 GAS8 Arina Puzriakova commented on gene: GAS8
Intellectual disability v3.252 GALK1 Arina Puzriakova commented on gene: GALK1
Intellectual disability v3.252 GAA Arina Puzriakova commented on gene: GAA
Intellectual disability v3.251 FZD6 Arina Puzriakova commented on gene: FZD6
Intellectual disability v3.251 FYCO1 Arina Puzriakova commented on gene: FYCO1
Intellectual disability v3.251 FXN Arina Puzriakova commented on gene: FXN
Intellectual disability v3.251 FTL Arina Puzriakova commented on gene: FTL
Intellectual disability v3.251 FOXN1 Arina Puzriakova commented on gene: FOXN1
Intellectual disability v3.251 FOXF1 Arina Puzriakova commented on gene: FOXF1
Intellectual disability v3.251 FOXE3 Arina Puzriakova commented on gene: FOXE3
Intellectual disability v3.251 FOXE1 Arina Puzriakova commented on gene: FOXE1
Intellectual disability v3.251 FOXC2 Arina Puzriakova commented on gene: FOXC2
Intellectual disability v3.251 FOXC1 Arina Puzriakova commented on gene: FOXC1
Intellectual disability v3.251 FLT4 Arina Puzriakova commented on gene: FLT4
Intellectual disability v3.251 FLNB Arina Puzriakova commented on gene: FLNB
Intellectual disability v3.251 FKBP14 Arina Puzriakova commented on gene: FKBP14
Intellectual disability v3.251 FHL1 Arina Puzriakova commented on gene: FHL1
Intellectual disability v3.251 FGF3 Arina Puzriakova commented on gene: FGF3
Intellectual disability v3.251 FGF10 Arina Puzriakova commented on gene: FGF10
Intellectual disability v3.251 FBXW4 Arina Puzriakova commented on gene: FBXW4
Intellectual disability v3.251 FBP1 Arina Puzriakova commented on gene: FBP1
Intellectual disability v3.251 FBN1 Arina Puzriakova commented on gene: FBN1
Intellectual disability v3.251 FAM20A Arina Puzriakova commented on gene: FAM20A
Intellectual disability v3.251 FAM161A Arina Puzriakova commented on gene: FAM161A
Intellectual disability v3.251 FAAH2 Arina Puzriakova commented on gene: FAAH2
Intellectual disability v3.251 EYA1 Arina Puzriakova commented on gene: EYA1
Intellectual disability v3.251 EVC2 Arina Puzriakova commented on gene: EVC2
Intellectual disability v3.251 EVC Arina Puzriakova commented on gene: EVC
Intellectual disability v3.251 ERMARD Arina Puzriakova commented on gene: ERMARD
Intellectual disability v3.251 ERF Arina Puzriakova commented on gene: ERF
Intellectual disability v3.251 ERCC4 Arina Puzriakova commented on gene: ERCC4
Intellectual disability v3.251 EOGT Arina Puzriakova commented on gene: EOGT
Intellectual disability v3.251 ENPP1 Arina Puzriakova commented on gene: ENPP1
Intellectual disability v3.251 ELN Arina Puzriakova commented on gene: ELN
Intellectual disability v3.251 EDNRA Arina Puzriakova commented on gene: EDNRA
Intellectual disability v3.251 EDA Arina Puzriakova commented on gene: EDA
Intellectual disability v3.251 ECEL1 Arina Puzriakova commented on gene: ECEL1
Intellectual disability v3.251 DYNC2H1 Arina Puzriakova commented on gene: DYNC2H1
Intellectual disability v3.251 DVL1 Arina Puzriakova commented on gene: DVL1
Intellectual disability v3.251 DSTYK Arina Puzriakova commented on gene: DSTYK
Intellectual disability v3.251 DSPP Arina Puzriakova commented on gene: DSPP
Intellectual disability v3.251 DPM3 Arina Puzriakova commented on gene: DPM3
Intellectual disability v3.251 DNAAF4 Arina Puzriakova commented on gene: DNAAF4
Intellectual disability v3.251 DNAAF3 Arina Puzriakova commented on gene: DNAAF3
Intellectual disability v3.251 DMP1 Arina Puzriakova commented on gene: DMP1
Intellectual disability v3.251 DLL4 Arina Puzriakova commented on gene: DLL4
Intellectual disability v3.251 DLL3 Arina Puzriakova commented on gene: DLL3
Intellectual disability v3.251 DDB2 Arina Puzriakova commented on gene: DDB2
Intellectual disability v3.251 DCC Arina Puzriakova commented on gene: DCC
Intellectual disability v3.251 CYP7B1 Arina Puzriakova commented on gene: CYP7B1
Intellectual disability v3.251 CYP1B1 Arina Puzriakova commented on gene: CYP1B1
Intellectual disability v3.251 CTSK Arina Puzriakova commented on gene: CTSK
Intellectual disability v3.251 CTSF Arina Puzriakova commented on gene: CTSF
Intellectual disability v3.250 CTNS Arina Puzriakova commented on gene: CTNS
Intellectual disability v3.250 CRYGD Arina Puzriakova commented on gene: CRYGD
Intellectual disability v3.250 CRYBB3 Arina Puzriakova commented on gene: CRYBB3
Intellectual disability v3.250 CRYBB2 Arina Puzriakova commented on gene: CRYBB2
Intellectual disability v3.250 CRYBB1 Arina Puzriakova commented on gene: CRYBB1
Intellectual disability v3.250 CRYBA1 Arina Puzriakova commented on gene: CRYBA1
Intellectual disability v3.250 CRYAA Arina Puzriakova commented on gene: CRYAA
Intellectual disability v3.250 CRX Arina Puzriakova commented on gene: CRX
Intellectual disability v3.250 CRB1 Arina Puzriakova commented on gene: CRB1
Intellectual disability v3.250 COMP Arina Puzriakova commented on gene: COMP
Intellectual disability v3.250 COL9A3 Arina Puzriakova commented on gene: COL9A3
Intellectual disability v3.250 COL9A2 Arina Puzriakova commented on gene: COL9A2
Intellectual disability v3.250 COL9A1 Arina Puzriakova commented on gene: COL9A1
Intellectual disability v3.250 COL6A1 Arina Puzriakova commented on gene: COL6A1
Intellectual disability v3.250 COL4A4 Arina Puzriakova commented on gene: COL4A4
Intellectual disability v3.250 COL4A3 Arina Puzriakova commented on gene: COL4A3
Intellectual disability v3.250 COL2A1 Arina Puzriakova commented on gene: COL2A1
Intellectual disability v3.250 COL1A1 Arina Puzriakova commented on gene: COL1A1
Intellectual disability v3.250 COL18A1 Arina Puzriakova commented on gene: COL18A1
Intellectual disability v3.250 COL11A1 Arina Puzriakova commented on gene: COL11A1
Intellectual disability v3.250 COL10A1 Arina Puzriakova commented on gene: COL10A1
Intellectual disability v3.250 CLDN19 Arina Puzriakova commented on gene: CLDN19
Intellectual disability v3.250 CLCN7 Arina Puzriakova commented on gene: CLCN7
Intellectual disability v3.250 CIB2 Arina Puzriakova commented on gene: CIB2
Intellectual disability v3.250 CHUK Arina Puzriakova commented on gene: CHUK
Intellectual disability v3.250 CHSY1 Arina Puzriakova commented on gene: CHSY1
Intellectual disability v3.250 CHST3 Arina Puzriakova commented on gene: CHST3
Intellectual disability v3.250 CHRNG Arina Puzriakova commented on gene: CHRNG
Intellectual disability v3.250 CHRDL1 Arina Puzriakova commented on gene: CHRDL1
Intellectual disability v3.250 CHM Arina Puzriakova commented on gene: CHM
Intellectual disability v3.250 CDH3 Arina Puzriakova commented on gene: CDH3
Intellectual disability v3.250 CDH23 Arina Puzriakova commented on gene: CDH23
Intellectual disability v3.250 CCT5 Arina Puzriakova commented on gene: CCT5
Intellectual disability v3.250 CCNO Arina Puzriakova commented on gene: CCNO
Intellectual disability v3.250 CCDC65 Arina Puzriakova commented on gene: CCDC65
Intellectual disability v3.250 CCDC40 Arina Puzriakova commented on gene: CCDC40
Intellectual disability v3.250 CCDC114 Arina Puzriakova commented on gene: CCDC114
Intellectual disability v3.250 CCDC103 Arina Puzriakova commented on gene: CCDC103
Intellectual disability v3.250 C4orf26 Arina Puzriakova commented on gene: C4orf26
Intellectual disability v3.250 C2orf71 Arina Puzriakova commented on gene: C2orf71
Intellectual disability v3.250 C19orf12 Arina Puzriakova commented on gene: C19orf12
Intellectual disability v3.250 BMPR1B Arina Puzriakova commented on gene: BMPR1B
Intellectual disability v3.250 BMPER Arina Puzriakova commented on gene: BMPER
Intellectual disability v3.250 BICD2 Arina Puzriakova commented on gene: BICD2
Intellectual disability v3.250 BHLHA9 Arina Puzriakova commented on gene: BHLHA9
Intellectual disability v3.250 BGN Arina Puzriakova commented on gene: BGN
Intellectual disability v3.250 BFSP2 Arina Puzriakova commented on gene: BFSP2
Intellectual disability v3.250 ATP8B1 Arina Puzriakova commented on gene: ATP8B1
Intellectual disability v3.250 ATP6V1B1 Arina Puzriakova commented on gene: ATP6V1B1
Intellectual disability v3.250 ARHGEF6 Arina Puzriakova commented on gene: ARHGEF6
Bleeding and platelet disorders v1.6 THBD Zornitza Stark reviewed gene: THBD: Rating: AMBER; Mode of pathogenicity: None; Publications: 25564403, 32634856; Phenotypes: Bleeding disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.6 PTGS1 Zornitza Stark reviewed gene: PTGS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32299908; Phenotypes: Platelet dysfunction, bleeding; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.6 PRKACG Zornitza Stark reviewed gene: PRKACG: Rating: RED; Mode of pathogenicity: None; Publications: 25061177, 30819905; Phenotypes: Bleeding disorder, platelet-type, 19, MIM# 616176; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.6 NBEA Zornitza Stark reviewed gene: NBEA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.6 KNG1 Zornitza Stark reviewed gene: KNG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bleeding and platelet disorders v1.6 KLKB1 Zornitza Stark reviewed gene: KLKB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fletcher factor (prekallikrein) deficiency, MIM# 612423; Mode of inheritance: None
Intellectual disability v3.249 ALDOB Arina Puzriakova commented on gene: ALDOB
Intellectual disability v3.249 AGL Arina Puzriakova commented on gene: AGL
Intellectual disability v3.249 ADGRG6 Arina Puzriakova commented on gene: ADGRG6
Intellectual disability v3.249 ADCY5 Arina Puzriakova commented on gene: ADCY5
Intellectual disability v3.249 ABCC6 Arina Puzriakova commented on gene: ABCC6
Intellectual disability v3.248 ACOX2 Arina Puzriakova Classified gene: ACOX2 as Red List (low evidence)
Intellectual disability v3.248 ACOX2 Arina Puzriakova Added comment: Comment on list classification: Rating Red - to date, only mild ID reported in a single patient.
Intellectual disability v3.248 ACOX2 Arina Puzriakova Gene: acox2 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 NCKAP1L Zornitza Stark edited their review of gene: NCKAP1L: Changed rating: GREEN
Intellectual disability v3.247 PDP1 Arina Puzriakova Classified gene: PDP1 as Amber List (moderate evidence)
Intellectual disability v3.247 PDP1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, given the mild delay in psychomotor development seen in these patients. This gene is Green on other panels which are more relevant to the phenotype.
Intellectual disability v3.247 PDP1 Arina Puzriakova Gene: pdp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.246 PDP1 Arina Puzriakova reviewed gene: PDP1: Rating: ; Mode of pathogenicity: None; Publications: 15855260, 19184109, 31392110; Phenotypes: Pyruvate dehydrogenase phosphatase deficiency, 608782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.246 PNPT1 Arina Puzriakova Tag for-review tag was added to gene: PNPT1.
Fetal hydrops v1.22 LARS2 Zornitza Stark edited their review of gene: LARS2: Set current diagnostic: yes
Fetal hydrops v1.22 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26537577, 32442335; Phenotypes: Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.246 PDHB Arina Puzriakova Publications for gene: PDHB were set to 15138885; 26014431
Intellectual disability v3.245 PDHB Arina Puzriakova Classified gene: PDHB as Amber List (moderate evidence)
Intellectual disability v3.245 PDHB Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - moderate ID/DD reported in multiple surviving patients.
Intellectual disability v3.245 PDHB Arina Puzriakova Gene: pdhb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.244 PDHB Arina Puzriakova Tag for-review tag was added to gene: PDHB.
Ichthyosis and erythrokeratoderma v1.3 TRPV3 Zornitza Stark reviewed gene: TRPV3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Olmsted syndrome, MIM# 614594; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.6 FYB1 Zornitza Stark reviewed gene: FYB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25516138, 25876182; Phenotypes: Thrombocytopenia 3, MIM# 273900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.6 FLNA Zornitza Stark reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 32299270; Phenotypes: ; Mode of inheritance: None
Bleeding and platelet disorders v1.6 F12 Zornitza Stark reviewed gene: F12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Factor XII deficiency, MIM# 234000; Mode of inheritance: None
Intellectual disability v3.244 CNTNAP1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Lethal congenital contracture syndrome 7 61628. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.
Intellectual disability v3.244 B9D2 Sarah Leigh commented on gene: B9D2: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.244 CNTNAP1 Sarah Leigh edited their review of gene: CNTNAP1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.244 CNTNAP1 Sarah Leigh Classified gene: CNTNAP1 as Amber List (moderate evidence)
Intellectual disability v3.244 CNTNAP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported four unrelated cases of Lethal congenital contracture syndrome 7 616286 and seven variants reported in four cases of Hypomyelinating neuropathy, congenital, 3 618186. Both of these conditions include intellectual disability.
Intellectual disability v3.244 CNTNAP1 Sarah Leigh Gene: cntnap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.243 CNTNAP1 Sarah Leigh Tag for-review tag was added to gene: CNTNAP1.
Intellectual disability v3.243 CNTNAP1 Sarah Leigh Phenotypes for gene: CNTNAP1 were changed from Hypomyelinating neuropathy, congenital, 3, MIM#618186; Lethal congenital contracture syndrome 7, MIM# 616286 to Hypomyelinating neuropathy, congenital, 3 618186; Lethal congenital contracture syndrome 7 616286
Intellectual disability v3.242 B9D2 Sarah Leigh edited their review of gene: B9D2: Added comment: Three variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment, together with supportive functional studies (PMID 21763481).; Changed rating: GREEN
Intellectual disability v3.242 B9D2 Sarah Leigh Deleted their comment
Intellectual disability v3.242 B9D2 Sarah Leigh Classified gene: B9D2 as Amber List (moderate evidence)
Intellectual disability v3.242 B9D2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in four unrelated cases. Three of the variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment and the remaining three variants were found in two unrelated fetuses with Meckel syndrome 10, with brain malformations.
Intellectual disability v3.242 B9D2 Sarah Leigh Gene: b9d2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.241 B9D2 Sarah Leigh Tag for-review tag was added to gene: B9D2.
Intellectual disability v3.241 B9D2 Sarah Leigh Phenotypes for gene: B9D2 were changed from Joubert syndrome 34, MIM#614175; Meckel syndrome 10, MIM#614175 to Joubert syndrome 34 614175; Meckel syndrome 10 614175
Intellectual disability v3.241 B9D2 Sarah Leigh Classified gene: B9D2 as Amber List (moderate evidence)
Intellectual disability v3.241 B9D2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in four unrelated cases. Three of the variants were reported in two unrelated cases of Joubert syndrome 34, which includes intellectual impairment and the remaining three variants were found in two unrelated fetuses with Meckel syndrome 10, with brain malformations.
Intellectual disability v3.241 B9D2 Sarah Leigh Gene: b9d2 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.6 IKZF5 Arina Puzriakova Classified gene: IKZF5 as Amber List (moderate evidence)
Bleeding and platelet disorders v1.6 IKZF5 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Bleeding and platelet disorders v1.6 IKZF5 Arina Puzriakova Gene: ikzf5 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.5 IKZF5 Arina Puzriakova Tag for-review tag was added to gene: IKZF5.
Bleeding and platelet disorders v1.5 AP3D1 Arina Puzriakova Classified gene: AP3D1 as Green List (high evidence)
Bleeding and platelet disorders v1.5 AP3D1 Arina Puzriakova Added comment: Comment on list classification: Green rating based on expert list/supporting information from the NIHRBR-RD BRIDGE project
Bleeding and platelet disorders v1.5 AP3D1 Arina Puzriakova Gene: ap3d1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 IVNS1ABP Arina Puzriakova Tag watchlist tag was added to gene: IVNS1ABP.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 IVNS1ABP Arina Puzriakova Classified gene: IVNS1ABP as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 IVNS1ABP Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of the possibility of incomplete penetrance, and uninformative segregation analysis in 2/3 cases. Awaiting additional publications/clinical evidence to validate association (added to watchlist).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 IVNS1ABP Arina Puzriakova Gene: ivns1abp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.183 IVNS1ABP Arina Puzriakova Tag for-review was removed from gene: IVNS1ABP.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.183 IVNS1ABP Arina Puzriakova Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v2.183 IVNS1ABP Arina Puzriakova edited their review of gene: IVNS1ABP: Changed rating: AMBER
COVID-19 research v1.68 IVNS1ABP Arina Puzriakova Classified gene: IVNS1ABP as Amber List (moderate evidence)
COVID-19 research v1.68 IVNS1ABP Arina Puzriakova Gene: ivns1abp has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.67 IVNS1ABP Arina Puzriakova edited their review of gene: IVNS1ABP: Changed rating: AMBER
Primary immunodeficiency or monogenic inflammatory bowel disease v2.183 NCKAP1L Arina Puzriakova Publications for gene: NCKAP1L were set to 32647003
Primary immunodeficiency or monogenic inflammatory bowel disease v2.182 NCKAP1L Arina Puzriakova Classified gene: NCKAP1L as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.182 NCKAP1L Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least six unrelated families with distinct variants in this gene presenting the relevant phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.182 NCKAP1L Arina Puzriakova Gene: nckap1l has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.181 NCKAP1L Arina Puzriakova Tag for-review tag was added to gene: NCKAP1L.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.181 NCKAP1L Arina Puzriakova reviewed gene: NCKAP1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32647003, 32766723; Phenotypes: Immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.240 B9D2 Sarah Leigh Publications for gene: B9D2 were set to 26092869; 21763481
Bleeding and platelet disorders v1.4 COL3A1 Zornitza Stark reviewed gene: COL3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, vascular type, MIM# 130050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Bleeding and platelet disorders v1.4 COL1A1 Zornitza Stark reviewed gene: COL1A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, arthrochalasia type, 1, MIM# 130060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.4 CHST14 Zornitza Stark reviewed gene: CHST14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1, MIM# 601776; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Childhood solid tumours v2.13 NOP10 Arina Puzriakova changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Homozygous NOP10 variant (c.100C>T, p.Arg34Trp) only reported once in 3 affected members of a consanguineous Saudi family (PMID: 17507419). The variant caused telomere shortening in homozygous and heterozygous carriers.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Homozygous NOP10 variant (c.100C>T, p.Arg34Trp) only reported once in 3 affected members of a consanguineous Saudi family (PMID: 17507419). Additional cases required before inclusion on a diagnostic panel.
Childhood solid tumours cancer susceptibility v1.13 NOP10 Arina Puzriakova Classified gene: NOP10 as Amber List (moderate evidence)
Childhood solid tumours cancer susceptibility v1.13 NOP10 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Homozygous NOP10 variant (c.100C>T, p.Arg34Trp) only reported once in 3 affected members of a consanguineous Saudi family (PMID: 17507419). Additional cases required before inclusion on a diagnostic panel.
Childhood solid tumours cancer susceptibility v1.13 NOP10 Arina Puzriakova Gene: nop10 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.4 AP3D1 Zornitza Stark reviewed gene: AP3D1: Rating: RED; Mode of pathogenicity: None; Publications: 30472485, 26744459; Phenotypes: Hermansky-Pudlak syndrome 10, MIM# 617050, Oculocutaneous albinism, Severe neutropaenia, Recurrent infections, Seizures, Hearing loss, Neurodevelopmental delay; Mode of inheritance: None
Epidermolysis bullosa and congenital skin fragility v1.3 SPINK5 Zornitza Stark reviewed gene: SPINK5: Rating: RED; Mode of pathogenicity: None; Publications: 27905021; Phenotypes: Netherton syndrome (MIM#256500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Epidermolysis bullosa and congenital skin fragility v1.3 DSG3 Zornitza Stark reviewed gene: DSG3: Rating: RED; Mode of pathogenicity: None; Publications: 30528827; Phenotypes: Mucosal blistering; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Epidermolysis bullosa and congenital skin fragility v1.3 EGFR Zornitza Stark reviewed gene: EGFR: Rating: RED; Mode of pathogenicity: None; Publications: 24691054; Phenotypes: Inflammatory skin and bowel disease, neonatal, 2 (MIM#616069); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.181 SOCS1 Arina Puzriakova Classified gene: SOCS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.181 SOCS1 Arina Puzriakova Gene: socs1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.180 PTPN2 Arina Puzriakova Classified gene: PTPN2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.180 PTPN2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional cases required for inclusion of PTPN2 on a diagnostic panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.180 PTPN2 Arina Puzriakova Gene: ptpn2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.67 IVNS1ABP Arina Puzriakova Classified gene: IVNS1ABP as Green List (high evidence)
COVID-19 research v1.67 IVNS1ABP Arina Puzriakova Gene: ivns1abp has been classified as Green List (High Evidence).
COVID-19 research v1.66 IVNS1ABP Arina Puzriakova reviewed gene: IVNS1ABP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32499645; Phenotypes: Immunodeficiency 70, 618969; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.179 IVNS1ABP Arina Puzriakova Tag for-review tag was added to gene: IVNS1ABP.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.179 IVNS1ABP Arina Puzriakova Phenotypes for gene: IVNS1ABP were changed from primary immunodeficiency to Immunodeficiency 70, MIM#618969
Primary immunodeficiency or monogenic inflammatory bowel disease v2.178 IVNS1ABP Arina Puzriakova Publications for gene: IVNS1ABP were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.177 IVNS1ABP Arina Puzriakova Mode of inheritance for gene: IVNS1ABP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.176 IVNS1ABP Arina Puzriakova Classified gene: IVNS1ABP as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.176 IVNS1ABP Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.176 IVNS1ABP Arina Puzriakova Gene: ivns1abp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 IVNS1ABP Arina Puzriakova reviewed gene: IVNS1ABP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32499645; Phenotypes: Immunodeficiency 70, 618969; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood solid tumours cancer susceptibility v1.12 DIS3L2 Arina Puzriakova Classified gene: DIS3L2 as Green List (high evidence)
Childhood solid tumours cancer susceptibility v1.12 DIS3L2 Arina Puzriakova Gene: dis3l2 has been classified as Green List (High Evidence).
Childhood solid tumours cancer susceptibility v1.11 BUB1B Arina Puzriakova Classified gene: BUB1B as Green List (high evidence)
Childhood solid tumours cancer susceptibility v1.11 BUB1B Arina Puzriakova Gene: bub1b has been classified as Green List (High Evidence).
Childhood solid tumours cancer susceptibility v1.10 HRAS Arina Puzriakova Classified gene: HRAS as Green List (high evidence)
Childhood solid tumours cancer susceptibility v1.10 HRAS Arina Puzriakova Gene: hras has been classified as Green List (High Evidence).
Childhood solid tumours v2.13 NOP10 Arina Puzriakova Publications for gene: NOP10 were set to 22965356
Childhood solid tumours v2.12 NOP10 Arina Puzriakova Classified gene: NOP10 as Amber List (moderate evidence)
Childhood solid tumours v2.12 NOP10 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Homozygous NOP10 variant (c.100C>T, p.Arg34Trp) only reported once in 3 affected members of a consanguineous Saudi family (PMID: 17507419). The variant caused telomere shortening in homozygous and heterozygous carriers.
Childhood solid tumours v2.12 NOP10 Arina Puzriakova Gene: nop10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.239 MADD Konstantinos Varvagiannis reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: Global developmental delay / Intellectual disability / Seizures, Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.143 MADD Konstantinos Varvagiannis gene: MADD was added
gene: MADD was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MADD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MADD were set to 28940097; 29302074; 32761064
Phenotypes for gene: MADD were set to Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system
Penetrance for gene: MADD were set to Complete
Review for gene: MADD was set to GREEN
Added comment: There are 3 reports on the phenotype of individuals with biallelic pathogenic MADD variants. Clinical presentation appears to be relevant for inclusion of this gene in both ID and epilepsy panels. A recent study provides extensive clinical details and suggests that the phenotype may range from DD/ID to a severe pleiotropic disorder characterized by severe DD (and ID), sensory and autonomic dysfunction, exocrine and endocrine insufficiency and haematological anomalies). Seizures have been reported in several individuals with either presentation.
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Anazi et al (2017 - PMID: 28940097) identified MADD as a potential ID gene. The authors described a girl with profound DD and seizures among other features. The child, deceased at the age of 14m, was born to consanguineous Saoudi parents and was found to harbour a homozygous missense SNV [NM_003682.3:c.2930T>G:p.(Val977Gly)]. Through GeneMatcher, the authors identified a further 6 y.o. girl, compound heterozygous for a missense and a stopgain variant [NM_003682.3:c.593G>A:p.(Arg198His) and c.979C>T:p.(Arg327*)]. The child had normal development and milestones until the age of 15m, when she demonstrated delay in speech, social interactions, poor eye contact and was later diagnosed with ASD.
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Hu et al (2019 - PMID: 29302074) provided details on a 22- and 30- y.o. female born to (reportedly) unrelated parents. Formal evaluation (WAIS-IV) suggested ID in the mild to moderate range(IQs of 50 and 60 respectively). Both were homozygous for an indel [NM_003682:c.3559del / p.(Met1187*)].
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Schneeberger et al (2020 - PMID: 32761064) report on 23 affected subjects.

The authors categorized the phenotypes in 2 groups. 9 individuals belonging to group 1 presented with hypotonia, DD (9/9) with speech impaiment, ID (5/5) and seizures (6/9). 14 patients, belonging to group 2 had DD (9/9 - severe), ID (3/3), seizures (9/14), endo- and exocrine dysfunction, impairment of sensory and autonomic nervous system, haematological anomalies. The course was fatal in some cases, within the later group. Some facial features appeared to be more frequent (e.g. full cheeks, small mouth, tented upper lip - small palpebral fissures in some, etc). Genital anomalies were also common in males from both groups.

All were found to harbor biallelic MADD variants (21 different - missense and pLoF SNVs as well as an intragenic deletion). Variants in all cases affected all 7 isoforms. Data did not allow genotype-phenotype correlations e.g. individuals with missense and a pLoF variant (in trans) were identified within either group.

Studies using patient-derived fibroblasts supported the role of the variants, e.g. lower mRNA levels for those where NMD would apply, deficiency or drastic reduction of the protein upon immunobloting (also the case for missense variants) and mRNA analyses demonstrating aberrant transcripts for 2 relevant variants.

MADD encodes the MAPK-activating protein containing a death domain implicated among others in neurotransmission (Rab3 GEF and effector playing a role in formation/trafficking of synaptic vessicles), cell survival (pro-apoptotic effects/protection against apoptosis upon TNF-a treatment), etc. The gene has relevant expression pattern in fetal and adult brain (discussed by Hu et al).

Studies in patient fibroblasts provide evidence of reduced activation of MAP kinases ERK1/2 upon treatment with TNF-a, activation of the intrinsic (TNF-a-dependent-) apoptosis. MADD deficiency was shown to result to decreased EGF endocytosis (likely mediated by Rab3).

Mouse model further supports the role of MADD (summary by MGI: "Mice homozygous for a knock-out allele die shortly after birth due to respiratory failure, are hyporesponsive to tactile stimuli, and exhibit defects in neurotransmitter release with impaired synaptic vesicle trafficking and depletion of synaptic vesicles at the neuromuscular junction.").

You may consider inclusion in other gene panels e.g. for hematologic (low Hb and thrombocytopenia in several) or GI (e.g diarrhea) disorders.
Sources: Literature
Cholestasis v1.16 UNC45A Zornitza Stark gene: UNC45A was added
gene: UNC45A was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: UNC45A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45A were set to 29429573
Phenotypes for gene: UNC45A were set to Cholestasis; Diarrhoea; Bone fragility; Impaired hearing
Review for gene: UNC45A was set to GREEN
gene: UNC45A was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Expert list
Cholestasis v1.16 TMEM67 Zornitza Stark reviewed gene: TMEM67: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Cholestasis v1.16 RPGRIP1L Zornitza Stark reviewed gene: RPGRIP1L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Cholestasis v1.16 PKHD1 Zornitza Stark gene: PKHD1 was added
gene: PKHD1 was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: PKHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKHD1 were set to 30366773; 25771912; 8616994
Phenotypes for gene: PKHD1 were set to Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200
Review for gene: PKHD1 was set to GREEN
gene: PKHD1 was marked as current diagnostic
Added comment: Periportal fibrosis is a key feature, cholestasis reported.
Sources: Expert list
Cholestasis v1.16 PEX14 Zornitza Stark gene: PEX14 was added
gene: PEX14 was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: PEX14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PEX14 were set to 21686775; 18285423
Phenotypes for gene: PEX14 were set to Peroxisome biogenesis disorder 13A (Zellweger), MIM# 614887
Review for gene: PEX14 was set to AMBER
Added comment: Two cases reported with cholestasis.
Sources: Expert list
Cholestasis v1.16 NPHP3 Zornitza Stark gene: NPHP3 was added
gene: NPHP3 was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: NPHP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPHP3 were set to 18371931; 20007846; 32341812
Phenotypes for gene: NPHP3 were set to Renal-hepatic-pancreatic dysplasia 1, MIM# 208540
Review for gene: NPHP3 was set to GREEN
Added comment: Very rare ciliopathy with prominent liver phenotype, including cholestasis.
Sources: Expert list
Cholestasis v1.16 NBAS Zornitza Stark reviewed gene: NBAS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Cholestasis v1.16 MPV17 Zornitza Stark gene: MPV17 was added
gene: MPV17 was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: MPV17 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MPV17 were set to Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), MIM# 256810
Review for gene: MPV17 was set to GREEN
gene: MPV17 was marked as current diagnostic
Added comment: Hepatic involvement is prominent, cholestasis described in addition to hepatomegaly, persistent neonatal jaundice, Reye-like syndrome, progressive hepatic failure.
Sources: Expert list
Cholestasis v1.16 IARS Zornitza Stark gene: IARS was added
gene: IARS was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: IARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IARS were set to 27426735; 27891590
Phenotypes for gene: IARS were set to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093
Review for gene: IARS was set to AMBER
Added comment: Liver dysfunction is variable, intermittent, and not present in all individuals reported. However, two individuals specifically reported as having cholestasis.
Sources: Expert list
Cholestasis v1.16 HNF1B Zornitza Stark gene: HNF1B was added
gene: HNF1B was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: HNF1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNF1B were set to 28324003; 29727438; 30791938; 25741167
Phenotypes for gene: HNF1B were set to Renal cysts and diabetes syndrome, MIM# 137920
Review for gene: HNF1B was set to GREEN
Added comment: Multiple case reports of cholestasis in individuals with HNF1B-related disease.
Sources: Expert list
Early onset or syndromic epilepsy v2.143 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to AMBER
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

The authors provide clinical details on 6 affected individuals from 5 families.

Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6).

In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam).

In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40).

Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3).

Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones).

Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt.

Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish.

Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins.

Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism.

Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Intellectual disability v3.239 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

The authors provide clinical details on 6 affected individuals from 5 families.

Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6).

In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam).

In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40).

Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3).

Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones).

Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt.

Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish.

Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins.

Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism.

Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Cholestasis v1.16 GBA Zornitza Stark gene: GBA was added
gene: GBA was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: GBA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBA were set to 32324335
Phenotypes for gene: GBA were set to Gaucher disease
Review for gene: GBA was set to GREEN
gene: GBA was marked as current diagnostic
Added comment: Ten cases reported presenting as neonatal cholestasis. Treatable metabolic disorder.
Sources: Expert list
Cholestasis v1.16 GALT Zornitza Stark gene: GALT was added
gene: GALT was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: GALT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALT were set to 30693370
Phenotypes for gene: GALT were set to Galactosemia, MIM# 230400
Review for gene: GALT was set to GREEN
Added comment: Liver disease, including cholestasis is a prominent part of the presenting phenotype of this relatively common, treatable metabolic disorder.
Sources: Expert list
Cholestasis v1.16 DGUOK Zornitza Stark gene: DGUOK was added
gene: DGUOK was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: DGUOK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DGUOK were set to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880
Review for gene: DGUOK was set to GREEN
gene: DGUOK was marked as current diagnostic
Added comment: Progressive liver disease including cholestasis is a prominent part of the presenting phenotype.
Sources: Expert list
Cholestasis v1.16 CYP7B1 Zornitza Stark reviewed gene: CYP7B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31337596, 30366773; Phenotypes: Bile acid synthesis defect, congenital, 3, MIM# 613812; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.16 CYP7A1 Zornitza Stark reviewed gene: CYP7A1: Rating: RED; Mode of pathogenicity: None; Publications: 9802883; Phenotypes: Cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.16 COG7 Zornitza Stark gene: COG7 was added
gene: COG7 was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: COG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG7 were set to 19577670; 17395513; 15107842
Phenotypes for gene: COG7 were set to Congenital disorder of glycosylation, type IIe , MIM#608779
Review for gene: COG7 was set to GREEN
Added comment: Hepatomegaly, abnormal LFTs, cholestasis reported in several affected individuals with this CDG, often as part of the initial presentation.
Sources: Expert list
Cholestasis v1.16 ATP7B Zornitza Stark gene: ATP7B was added
gene: ATP7B was added to Cholestasis. Sources: Expert list
Mode of inheritance for gene: ATP7B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP7B were set to Wilson disease, MIM# 277900
Review for gene: ATP7B was set to GREEN
gene: ATP7B was marked as current diagnostic
Added comment: Although the classic presentation of Wilson's disease is with hepatitis or liver failure, consider including in this panel as a relatively common, treatable cause of liver disease.
Sources: Expert list
Hypophosphataemia or rickets v2.5 OCRL Zornitza Stark gene: OCRL was added
gene: OCRL was added to Hypophosphataemia or rickets. Sources: Expert list
Mode of inheritance for gene: OCRL was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OCRL were set to 19773212
Phenotypes for gene: OCRL were set to Lowe syndrome, MIM# 309000
Review for gene: OCRL was set to GREEN
Added comment: Renal rickets is a complication of Lowe syndrome.
Sources: Expert list
Hypophosphataemia or rickets v2.5 FAH Zornitza Stark gene: FAH was added
gene: FAH was added to Hypophosphataemia or rickets. Sources: Expert list
Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAH were set to Tyrosinemia, type I, MIM# 276700
Review for gene: FAH was set to GREEN
Added comment: Hypophosphataemic rickets is a feature of this metabolic disorder.
Sources: Expert list
Hypophosphataemia or rickets v2.5 SGK3 Zornitza Stark gene: SGK3 was added
gene: SGK3 was added to Hypophosphataemia or rickets. Sources: Literature
Mode of inheritance for gene: SGK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGK3 were set to 31821448
Phenotypes for gene: SGK3 were set to Hypophosphatemic rickets
Review for gene: SGK3 was set to RED
Added comment: 5 individuals from one family where a splice site variant segregated with disease.
Sources: Literature
Hypophosphataemia or rickets v2.5 ALPL Zornitza Stark gene: ALPL was added
gene: ALPL was added to Hypophosphataemia or rickets. Sources: Expert list
Mode of inheritance for gene: ALPL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALPL were set to Hypophosphatasia, infantile, MIM# 241500
Review for gene: ALPL was set to GREEN
Added comment: Fractures, poor mineralisation, rachitic rosary.
Sources: Expert list
Hydrocephalus v2.5 TNFRSF11A Zornitza Stark gene: TNFRSF11A was added
gene: TNFRSF11A was added to Hydrocephalus. Sources: Expert list
Mode of inheritance for gene: TNFRSF11A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TNFRSF11A were set to Osteopetrosis, autosomal recessive 7, MIM# 612301
Review for gene: TNFRSF11A was set to GREEN
gene: TNFRSF11A was marked as current diagnostic
Added comment: Hydrocephalus is a reported feature.
Sources: Expert list
Hydrocephalus v2.5 TCIRG1 Zornitza Stark gene: TCIRG1 was added
gene: TCIRG1 was added to Hydrocephalus. Sources: Expert list
Mode of inheritance for gene: TCIRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TCIRG1 were set to Osteopetrosis, autosomal recessive 1, MIM# 259700
Review for gene: TCIRG1 was set to GREEN
Added comment: Hydrocephalus is a reported part of the phenotype.
Sources: Expert list
Hydrocephalus v2.5 TBC1D7 Zornitza Stark reviewed gene: TBC1D7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.5 SEC24D Zornitza Stark changed review comment from: Three further families reported.; to: Three further families reported, at least one (30462379) specifically had hydrocephalus.
Hydrocephalus v2.5 SEC24D Zornitza Stark reviewed gene: SEC24D: Rating: GREEN; Mode of pathogenicity: None; Publications: 30462379, 27942778, 26467156; Phenotypes: Cole-Carpenter syndrome 2, MIM# 616294; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus v2.5 P4HB Zornitza Stark reviewed gene: P4HB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30063094, 29263160, 25683117, 29384951; Phenotypes: Cole-Carpenter syndrome 1, MIM#112240; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Hydrocephalus v2.5 MYMK Zornitza Stark reviewed gene: MYMK: Rating: RED; Mode of pathogenicity: None; Publications: 28681861; Phenotypes: Carey-Fineman-Ziter syndrome, OMIM #254940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus v2.5 MPDZ Zornitza Stark reviewed gene: MPDZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 28556411, 23240096, 30518636, 29499638; Phenotypes: Hydrocephalus, congenital, 2, with or without brain or eye anomalies 615219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus v2.5 KIF7 Zornitza Stark reviewed gene: KIF7: Rating: AMBER; Mode of pathogenicity: None; Publications: 26174511; Phenotypes: Hydrolethalus syndrome 2, MIM# 614120, Ciliopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus v2.5 ISLR2 Zornitza Stark gene: ISLR2 was added
gene: ISLR2 was added to Hydrocephalus. Sources: Expert list
Mode of inheritance for gene: ISLR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISLR2 were set to 30483960
Phenotypes for gene: ISLR2 were set to hydrocephalus; arthrogryposis; abdominal distension
Review for gene: ISLR2 was set to AMBER
Added comment: single consanguineous family with hydrocephalus and arthrogryposis and homozygous truncating variant, mouse model has hydrocephalus
Sources: Expert list
Hydrocephalus v2.5 HYLS1 Zornitza Stark reviewed gene: HYLS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 15843405, 18648327, 19400947, 19656802, 32509774; Phenotypes: Hydrolethalus syndrome (MIM#236680); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus v2.5 ERF Zornitza Stark reviewed gene: ERF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis 4, MIM# 600775; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v1.5 MRAS Zornitza Stark gene: MRAS was added
gene: MRAS was added to Cardiomyopathies - including childhood onset. Sources: Expert list
Mode of inheritance for gene: MRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAS were set to 28289718; 31173466; 31108500; 31173466
Phenotypes for gene: MRAS were set to Noonan syndrome, MIM#618499
Mode of pathogenicity for gene: MRAS was set to Other
Review for gene: MRAS was set to GREEN
gene: MRAS was marked as current diagnostic
Added comment: At least 6 unrelated individuals reported with NS, cardiomyopathy specifically reported.
Sources: Expert list
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Tag for-review tag was added to gene: TET3.
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh edited their review of gene: TET3: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Added comment: Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#). to Beck-Fahrner syndrome 618798
Early onset or syndromic epilepsy v2.142 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face to This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Classified gene: TET3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Seizures were reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Gene: tet3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.140 TET3 Sarah Leigh Tag watchlist tag was added to gene: TET3.
Early onset or syndromic epilepsy v2.140 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Intellectual disability v3.239 TET3 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype including mild to severe intellectual disability in OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases.; to: Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Mild to severe intellectual disability was reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.
Early onset or syndromic epilepsy v2.139 TET3 Sarah Leigh Mode of inheritance for gene: TET3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.239 TET3 Sarah Leigh commented on gene: TET3: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.239 TET3 Sarah Leigh Classified gene: TET3 as Amber List (moderate evidence)
Intellectual disability v3.239 TET3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype including mild to severe intellectual disability in OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases.
Intellectual disability v3.239 TET3 Sarah Leigh Gene: tet3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.239 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Intellectual disability v3.238 TET3 Sarah Leigh Tag for-review tag was added to gene: TET3.
Intellectual disability v3.238 TET3 Sarah Leigh Added comment: Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Intellectual disability v3.238 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face to Beck-Fahrner syndrome 618798
Intellectual disability v3.237 AFF3 Sarah Leigh reviewed gene: AFF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.237 AFF3 Sarah Leigh Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733
Early onset or syndromic epilepsy v2.138 AFF3 Sarah Leigh Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733
Intellectual disability v3.236 SUZ12 Sarah Leigh Phenotypes for gene: SUZ12 were changed from Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall to Imagawa-Matsumoto syndrome 618786
Intellectual disability v3.235 SUZ12 Sarah Leigh Classified gene: SUZ12 as Amber List (moderate evidence)
Intellectual disability v3.235 SUZ12 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families, of whome 7 had mostly mild intellectual disability.
Intellectual disability v3.235 SUZ12 Sarah Leigh Gene: suz12 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.234 SUZ12 Sarah Leigh Tag for-review tag was added to gene: SUZ12.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh edited their review of gene: OXR1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.234 OXR1 Sarah Leigh edited their review of gene: OXR1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.234 OXR1 Sarah Leigh Classified gene: OXR1 as Amber List (moderate evidence)
Intellectual disability v3.234 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Intellectual disability v3.234 OXR1 Sarah Leigh Gene: oxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.234 OXR1 Sarah Leigh Tag for-review tag was added to gene: OXR1.
Intellectual disability v3.234 OXR1 Sarah Leigh Classified gene: OXR1 as Amber List (moderate evidence)
Intellectual disability v3.234 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Intellectual disability v3.234 OXR1 Sarah Leigh Gene: oxr1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Tag for-review tag was added to gene: OXR1.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Classified gene: OXR1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Gene: oxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.233 OXR1 Sarah Leigh Publications for gene: OXR1 were set to 31785787
Early onset or syndromic epilepsy v2.136 OXR1 Sarah Leigh Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Early onset or syndromic epilepsy v2.135 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Intellectual disability v3.232 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Intellectual disability v3.231 OXR1 Sarah Leigh Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Intellectual disability v3.230 SFXN4 Sarah Leigh Classified gene: SFXN4 as Amber List (moderate evidence)
Intellectual disability v3.230 SFXN4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 3 unreleated cases, with mild to severe intellectual disability.
Intellectual disability v3.230 SFXN4 Sarah Leigh Gene: sfxn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.229 SFXN4 Sarah Leigh Tag for-review tag was added to gene: SFXN4.
Intellectual disability v3.229 SFXN4 Sarah Leigh Phenotypes for gene: SFXN4 were changed from Combined oxidative phosphorylation deficiency 18, MIM#615578 to Combined oxidative phosphorylation deficiency 18 615578
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh edited their review of gene: MTHFS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.228 MTHFS Sarah Leigh edited their review of gene: MTHFS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.228 MTHFS Sarah Leigh Tag for-review tag was added to gene: MTHFS.
Intellectual disability v3.228 MTHFS Sarah Leigh Classified gene: MTHFS as Amber List (moderate evidence)
Intellectual disability v3.228 MTHFS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases.
Intellectual disability v3.228 MTHFS Sarah Leigh Gene: mthfs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Tag for-review tag was added to gene: MTHFS.
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Classified gene: MTHFS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases.
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Gene: mthfs has been classified as Amber List (Moderate Evidence).
Cholestasis v1.16 YARS Sarah Leigh Tag watchlist tag was added to gene: YARS.
Cholestasis v1.16 YARS Sarah Leigh commented on gene: YARS: The new gene for YARS is YARS1
Monogenic hearing loss v2.40 YARS Sarah Leigh commented on gene: YARS: The new gene for YARS is YARS1
Monogenic hearing loss v2.40 YARS Sarah Leigh Tag watchlist tag was added to gene: YARS.
Monogenic hearing loss v2.40 YARS Sarah Leigh Classified gene: YARS as Amber List (moderate evidence)
Monogenic hearing loss v2.40 YARS Sarah Leigh Gene: yars has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.39 YARS Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants are associated with Charcot-Marie-Tooth disease, dominant intermediate C 608323, while biallelic variants are associated with a complex phenotype that may include intellectual disability, hearing loss and liver damage.
Monogenic hearing loss v2.39 YARS Sarah Leigh Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Cholestasis v1.16 YARS Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants are associated with Charcot-Marie-Tooth disease, dominant intermediate C 608323, while biallelic variants are associated with a complex phenotype that may include intellectual disability, hearing loss and liver damage.
Cholestasis v1.16 YARS Sarah Leigh Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Cholestasis v1.15 YARS Sarah Leigh Classified gene: YARS as Amber List (moderate evidence)
Cholestasis v1.15 YARS Sarah Leigh Gene: yars has been classified as Amber List (Moderate Evidence).
Cholestasis v1.14 YARS Sarah Leigh Tag for-review tag was added to gene: YARS.
Cholestasis v1.14 YARS Sarah Leigh gene: YARS was added
gene: YARS was added to Cholestasis. Sources: Literature
new-gene-name tags were added to gene: YARS.
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to 30304524; 29232904; 27633801
Phenotypes for gene: YARS were set to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Review for gene: YARS was set to AMBER
Added comment: Biallelic variants in three families with complex clinical conditions including developmental delay and liver damage. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, cholestatic liver disease, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa, hypotonia, transiant fatty liver, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia and liver dysfunction. The older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level.
Sources: Literature
Monogenic hearing loss v2.38 YARS Sarah Leigh gene: YARS was added
gene: YARS was added to Hearing loss. Sources: Literature
new-gene-name tags were added to gene: YARS.
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to 30304524; 29232904; 27633801
Phenotypes for gene: YARS were set to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Review for gene: YARS was set to AMBER
Added comment: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level, but not hearing loss was reported.
Sources: Literature
Intellectual disability v3.227 YARS Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants are associated with Charcot-Marie-Tooth disease, dominant intermediate C 608323, while biallelic variants are associated with a complex phenotype that may include intellectual disability, hearing loss and liver damage.
Intellectual disability v3.227 YARS Sarah Leigh Phenotypes for gene: YARS were changed from Intellectual disability; deafness; nystagmus; liver dysfunction to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction
Intellectual disability v3.226 YARS Sarah Leigh Tag watchlist tag was added to gene: YARS.
Intracerebral calcification disorders v1.21 NRROS Sarah Leigh Classified gene: NRROS as Green List (high evidence)
Intracerebral calcification disorders v1.21 NRROS Sarah Leigh Added comment: Comment on list classification: sufficient evidence for this gene to be green.
Intracerebral calcification disorders v1.21 NRROS Sarah Leigh Gene: nrros has been classified as Green List (High Evidence).
Intracerebral calcification disorders v1.20 NRROS Sarah Leigh gene: NRROS was added
gene: NRROS was added to Intracerebral calcification disorders. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075; 28459434
Phenotypes for gene: NRROS were set to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Review for gene: NRROS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Sources: Literature
Intellectual disability v3.226 NRROS Sarah Leigh Tag for-review tag was added to gene: NRROS.
Pulmonary arterial hypertension v2.5 SARS2 Sarah Leigh edited their review of gene: SARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Unexplained kidney failure in young people v1.91 SARS2 Sarah Leigh edited their review of gene: SARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Renal tubulopathies v2.15 SARS2 Sarah Leigh edited their review of gene: SARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Renal tubulopathies v2.15 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Renal tubulopathies v2.15 SARS2 Sarah Leigh Added comment: Comment on list classification: Associated with Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845 in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional studies and segregation with the phenotype.
Renal tubulopathies v2.15 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.14 SARS2 Sarah Leigh Tag for-review tag was added to gene: SARS2.
Unexplained kidney failure in young people v1.91 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Unexplained kidney failure in young people v1.91 SARS2 Sarah Leigh Added comment: Comment on list classification: Associated with Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845 in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional studies and segregation with the phenotype.
Unexplained kidney failure in young people v1.91 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Unexplained kidney failure in young people v1.90 SARS2 Sarah Leigh Tag for-review tag was added to gene: SARS2.
Pulmonary arterial hypertension v2.5 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.5 SARS2 Sarah Leigh Added comment: Comment on list classification: Associated with Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845 in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional studies and segregation with the phenotype.
Pulmonary arterial hypertension v2.5 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.4 SARS2 Sarah Leigh Tag for-review tag was added to gene: SARS2.
Unexplained kidney failure in young people v1.90 SARS2 Sarah Leigh gene: SARS2 was added
gene: SARS2 was added to Unexplained kidney failure in young people. Sources: Literature
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276; 27279129
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845; Progressive Spastic Paresis
Review for gene: SARS2 was set to AMBER
Added comment: Sources: Literature
Renal tubulopathies v2.14 SARS2 Sarah Leigh gene: SARS2 was added
gene: SARS2 was added to Renal tubulopathies. Sources: Literature
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276; 27279129
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845; Progressive Spastic Paresis
Review for gene: SARS2 was set to AMBER
Added comment: Sources: Literature
Childhood solid tumours v2.11 ELP1 Arina Puzriakova Classified gene: ELP1 as Amber List (moderate evidence)
Childhood solid tumours v2.11 ELP1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to to rated GREEN at the next major review.
Childhood solid tumours v2.11 ELP1 Arina Puzriakova Gene: elp1 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v2.10 ELP1 Arina Puzriakova Tag for-review tag was added to gene: ELP1.
Childhood solid tumours v2.10 ELP1 Arina Puzriakova gene: ELP1 was added
gene: ELP1 was added to Tumour predisposition - childhood onset. Sources: Literature
Mode of inheritance for gene: ELP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ELP1 were set to 32296180
Phenotypes for gene: ELP1 were set to Medulloblastoma predisposition
Review for gene: ELP1 was set to GREEN
Added comment: PMID: 32296180 (2020) - Recurrent germline LOF variants of ELP1 detected in paediatric medulloblastoma (MB) cases; specifically the Sonic Hedgehog (SHH) subgroup, in which the variants were found in 14.4% (29/202) of patients. Inheritance of germline ELP1 LOF variants was confirmed by WES of three parent-offspring trios, two of which exhibited a family history of paediatric MB. Carriers of these variants tended to develop MB(SHH) as older children (median age at diagnosis: 6.3 years). ELP1-associated MB(SHH) tumours were significantly enriched for somatic alterations of PTCH1 (Sonic Hedgehog receptor), suggesting ELP1 LOF variants predispose to tumour development in combination with constitutive activation of SHH signalling.
Sources: Literature
Childhood solid tumours v2.9 GPR161 Arina Puzriakova Classified gene: GPR161 as Amber List (moderate evidence)
Childhood solid tumours v2.9 GPR161 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood solid tumours v2.9 GPR161 Arina Puzriakova Gene: gpr161 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v2.8 GPR161 Arina Puzriakova Tag for-review tag was added to gene: GPR161.
Childhood solid tumours v2.8 GPR161 Arina Puzriakova gene: GPR161 was added
gene: GPR161 was added to Tumour predisposition - childhood onset. Sources: Literature
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GPR161 were set to 29386106; 31609649
Phenotypes for gene: GPR161 were set to Medulloblastoma predisposition
Review for gene: GPR161 was set to GREEN
Added comment: PMID: 31609649 (2020) - Heterozygous germline variants were identified in 6 unrelated patients with infant-onset sonic hedgehog medulloblastoma (median age, 1.5 years). No additional germline or somatic driver events were detected. 5/6 cases demonstrated biallelic inactivation of GPR151 as a result of a somatic copy-neutral loss of heterozygosity event on chromosome 1q. This event was absent among GPR161 wild-type medulloblastoma tumours.

PMID: 29386106 (2018) - Loss of Gpr161 activity was consistent with medulloblastoma pathogenesis in a mouse model, where Gpr161 deletion increased downstream activity of the sonic hedgehog pathway. Earlier deletion of Gpr161 during embryogenesis increased tumour incidence and severity.
Sources: Literature
Childhood solid tumours cancer susceptibility v1.9 TRIP13 Arina Puzriakova Classified gene: TRIP13 as Green List (high evidence)
Childhood solid tumours cancer susceptibility v1.9 TRIP13 Arina Puzriakova Gene: trip13 has been classified as Green List (High Evidence).
Hereditary spastic paraplegia, childhood onset v2.14 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.14 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia v1.217 SARS2 Sarah Leigh Classified gene: SARS2 as Amber List (moderate evidence)
Hereditary spastic paraplegia v1.217 SARS2 Sarah Leigh Gene: sars2 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia v1.216 SARS2 Sarah Leigh gene: SARS2 was added
gene: SARS2 was added to Hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276; 27279129
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845; Progressive Spastic Paresis
Review for gene: SARS2 was set to AMBER
Added comment: PMID 27279129 reports a child with progressive spastic paresis with a homozygous splicing variant (c.1347G>A (NM_017827.3)), which was shown in vitro to result in retention of intron 14 and premature chain termination, leading to diminished levels of the synthetase in patient's fibroblasts.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.13 SARS2 Sarah Leigh gene: SARS2 was added
gene: SARS2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276; 27279129
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845; Progressive Spastic Paresis
Review for gene: SARS2 was set to AMBER
Added comment: PMID 27279129 reports a child with progressive spastic paresis with a homozygous splicing variant (c.1347G>A (NM_017827.3)), which was shown in vitro to result in retention of intron 14 and premature chain termination, leading to diminished levels of the synthetase in patient's fibroblasts.
Sources: Literature
Radial dysplasia v1.12 NPM1 Arina Puzriakova Mode of inheritance for gene: NPM1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Unknown
Radial dysplasia v1.11 NPM1 Arina Puzriakova Classified gene: NPM1 as Red List (low evidence)
Radial dysplasia v1.11 NPM1 Arina Puzriakova Added comment: Comment on list classification: Rated Red as skeletal abnormalities in the radius only observed in one patient. Additional cases required to corroborate causality and better define the phenotype. Both variants currently classified VUS - no information regarding segregation or zygosity.
Radial dysplasia v1.11 NPM1 Arina Puzriakova Gene: npm1 has been classified as Red List (Low Evidence).
Radial dysplasia v1.10 NPM1 Arina Puzriakova reviewed gene: NPM1: Rating: ; Mode of pathogenicity: None; Publications: 31570891; Phenotypes: Dyskeratosis congenita; Mode of inheritance: Unknown
Cytopenias and congenital anaemias v1.74 NPM1 Arina Puzriakova Classified gene: NPM1 as Amber List (moderate evidence)
Cytopenias and congenital anaemias v1.74 NPM1 Arina Puzriakova Added comment: Comment on list classification: Rated Amber as additional cases required to corroborate causality and better define the phenotype. Both variants currently classified VUS - no information regarding segregation or zygosity.
Cytopenias and congenital anaemias v1.74 NPM1 Arina Puzriakova Gene: npm1 has been classified as Amber List (Moderate Evidence).
Cytopenias and congenital anaemias v1.73 NPM1 Arina Puzriakova reviewed gene: NPM1: Rating: ; Mode of pathogenicity: None; Publications: 31570891; Phenotypes: Dyskeratosis congenita; Mode of inheritance: Unknown
RASopathies v1.61 RRAS Arina Puzriakova Classified gene: RRAS as Amber List (moderate evidence)
RASopathies v1.61 RRAS Arina Puzriakova Added comment: Comment on list classification: Rated Amber as additional cases required to validate the causal association with the phenotype.

Currently not associated with any phenotype in OMIM but a probable gene for Atypical Noonan Syndrome in G2P.
RASopathies v1.61 RRAS Arina Puzriakova Gene: rras has been classified as Amber List (Moderate Evidence).
RASopathies v1.60 RRAS2 Arina Puzriakova Added comment: Comment on mode of pathogenicity: All variants reported increase activation of the MAPK cascade.
RASopathies v1.60 RRAS2 Arina Puzriakova Mode of pathogenicity for gene: RRAS2 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
RASopathies v1.59 RRAS2 Arina Puzriakova Classified gene: RRAS2 as Green List (high evidence)
RASopathies v1.59 RRAS2 Arina Puzriakova Added comment: Comment on list classification: At least nine unrelated pedigrees with Noonan syndrome, associated with monoallelic variants in this gene.
RASopathies v1.59 RRAS2 Arina Puzriakova Gene: rras2 has been classified as Green List (High Evidence).
RASopathies v1.58 RRAS2 Arina Puzriakova reviewed gene: RRAS2: 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: 31130282, 31130285; Phenotypes: Noonan syndrome 12, 618624; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
RASopathies v1.58 RASA2 Arina Puzriakova Publications for gene: RASA2 were set to PMID: 25049390
RASopathies v1.57 RASA2 Arina Puzriakova Classified gene: RASA2 as Amber List (moderate evidence)
RASopathies v1.57 RASA2 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases but very limited details and no segregation data. Not associated with any phenotype in OMIM or G2P. Rated Amber, awaiting additional publications/clinical evidence to corroborate causality.
RASopathies v1.57 RASA2 Arina Puzriakova Gene: rasa2 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.4 IKZF5 Kate Downes changed review comment from: Lentaigne C, et al., 2019 details the association of thrombocytopenia with missense variants in the IKZF5 transcription factor. Five different missense variants in or near the IKZF5 zinc finger domains are reported in five independent probands. Co-segregation studies indicate that two variants occurred de novo and three co-segregate across large pedigrees.
Mode of pathogenicity is unknown.
Sources: Expert Review, Literature; to: Lentaigne C, et al., 2019 (PMID - 31217188) details the association of thrombocytopenia with missense variants in the IKZF5 transcription factor. Five different missense variants in or near the IKZF5 zinc finger domains are reported in five independent probands. Co-segregation studies indicate that two variants occurred de novo and three co-segregate across large pedigrees.
Mode of pathogenicity is unknown.
Sources: Expert Review, Literature
Bleeding and platelet disorders v1.4 IKZF5 Kate Downes changed review comment from: Lentaigne C, et al., 2019 details the association of thrombocytopenia with missense variants in the IKZF5 transcription factor. Five different missense variants in or near the IKZF5 zinc finger domains are reported in five independent probands. Co-segregation studies indicate that two variants occurred de novo and three co-segregate across large pedigrees.
Mode of pathogenicity is unknown.
Sources: Expert Review, Literature; to: Lentaigne C, et al., 2019 details the association of thrombocytopenia with missense variants in the IKZF5 transcription factor. Five different missense variants in or near the IKZF5 zinc finger domains are reported in five independent probands. Co-segregation studies indicate that two variants occurred de novo and three co-segregate across large pedigrees.
Mode of pathogenicity is unknown.
Sources: Expert Review, Literature
RASopathies v1.56 MRAS Arina Puzriakova Classified gene: MRAS as Green List (high evidence)
RASopathies v1.56 MRAS Arina Puzriakova Gene: mras has been classified as Green List (High Evidence).
RASopathies v1.55 MRAS Arina Puzriakova changed review comment from: PMID: 28289718 (2017) - In two unrelated patients with Noonan syndrome and cardiac hypertrophy, trio WES/targeted sequencing revealed de novo missense variants (c.68G>T, p.G23V and c.203C>T, p.T68I) in the MRAS gene. Functional studies of the p.Gly23Val variant showed the change yields a constitutively active form of MRAS.

PMID: 31173466 (2019) - One patient with a severe a Noonan syndrome phenotype, associated with a de novo MRAS variant (c.212A>G, p.Q71R). Functional studies were not performed.

PMID: 31108500 (2020) - Two unrelated patients with Noonan syndrome, including hypertrophic cardiomyopathy and dysmorphic features. Targeted sequencing revealed de novo activating MRAS variants (c.203C>T, p.T68I and c.67G>C, p.G23R). Functional studies demonstrated that the variants yields a constitutively active form of MRAS.; to: Associated with Noonan syndrome in OMIM and G2P (confirmed).

PMID: 28289718 (2017) - In two unrelated patients with Noonan syndrome and cardiac hypertrophy, trio WES/targeted sequencing revealed de novo missense variants (c.68G>T, p.G23V and c.203C>T, p.T68I) in the MRAS gene. Functional studies of the p.Gly23Val variant showed the change yields a constitutively active form of MRAS.

PMID: 31173466 (2019) - One patient with a severe a Noonan syndrome phenotype, associated with a de novo MRAS variant (c.212A>G, p.Q71R). Functional studies were not performed.

PMID: 31108500 (2020) - Two unrelated patients with Noonan syndrome, including hypertrophic cardiomyopathy and dysmorphic features. Targeted sequencing revealed de novo activating MRAS variants (c.203C>T, p.T68I and c.67G>C, p.G23R). Functional studies demonstrated that the variants yields a constitutively active form of MRAS.
RASopathies v1.55 MRAS Arina Puzriakova reviewed gene: MRAS: 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: 28289718, 31173466, 31108500; Phenotypes: Noonan syndrome 11, 618499; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic right ventricular cardiomyopathy v2.7 RYR2 Ivone Leong commented on gene: RYR2: Have tagged with "for-review" for the next major review of the panel.
Arrhythmogenic right ventricular cardiomyopathy v2.7 RYR2 Ivone Leong Tag for-review tag was added to gene: RYR2.
Arrhythmogenic right ventricular cardiomyopathy v2.7 CDH2 Ivone Leong Phenotypes for gene: CDH2 were changed from to Arrhythmogenic right ventricular dysplasia, familial, 14, 618920
Cholestasis v1.13 NBAS Ivone Leong changed review comment from: There are >3 unrelated cases of patients with variants in NBAS with infantile liver failure. Variants in this gene causes a wide range of symptoms that affect the liver, skeletal system and eyes.
Sources: Literature; to: There are >3 unrelated cases of patients with variants in NBAS with infantile liver failure. Variants in this gene causes a wide range of symptoms that affect the liver, skeletal system and eyes. This gene has been given an Amber review and tagged with "for-review" for the next major update of this panel.
Sources: Literature
Cholestasis v1.13 NBAS Ivone Leong Publications for gene: NBAS were set to 26541327, 28629372, 30622725, 26073778, 32146038, 31761904
Cholestasis v1.12 NBAS Ivone Leong Classified gene: NBAS as Amber List (moderate evidence)
Cholestasis v1.12 NBAS Ivone Leong Gene: nbas has been classified as Amber List (Moderate Evidence).
Cholestasis v1.11 NBAS Ivone Leong gene: NBAS was added
gene: NBAS was added to Cholestasis. Sources: Literature
for-review tags were added to gene: NBAS.
Mode of inheritance for gene: NBAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NBAS were set to 26541327, 28629372, 30622725, 26073778, 32146038, 31761904
Phenotypes for gene: NBAS were set to Infantile liver failure syndrome 2, 616483
Review for gene: NBAS was set to AMBER
Added comment: There are >3 unrelated cases of patients with variants in NBAS with infantile liver failure. Variants in this gene causes a wide range of symptoms that affect the liver, skeletal system and eyes.
Sources: Literature
Genodermatoses with malignancies v1.6 PTCH2 Ivone Leong reviewed gene: PTCH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood solid tumours cancer susceptibility v1.8 GPR161 Arina Puzriakova edited their review of gene: GPR161: Changed publications: 31609649, 29386106
Childhood solid tumours cancer susceptibility v1.8 GPR161 Arina Puzriakova Classified gene: GPR161 as Green List (high evidence)
Childhood solid tumours cancer susceptibility v1.8 GPR161 Arina Puzriakova Gene: gpr161 has been classified as Green List (High Evidence).
Childhood solid tumours cancer susceptibility v1.7 GPR161 Arina Puzriakova reviewed gene: GPR161: Rating: GREEN; Mode of pathogenicity: None; Publications: 31609649; Phenotypes: Medulloblastoma predisposition; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood solid tumours cancer susceptibility v1.7 ELP1 Arina Puzriakova Classified gene: ELP1 as Green List (high evidence)
Childhood solid tumours cancer susceptibility v1.7 ELP1 Arina Puzriakova Gene: elp1 has been classified as Green List (High Evidence).
Childhood solid tumours cancer susceptibility v1.6 ELP1 Arina Puzriakova reviewed gene: ELP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32296180; Phenotypes: Medulloblastoma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mitochondrial disorders v2.8 NDUFA8 Zornitza Stark reviewed gene: NDUFA8: Rating: RED; Mode of pathogenicity: None; Publications: 32385911; Phenotypes: NDUFA8-related mitochondrial disease, Developmental delay, microcehaly, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.26 DLG5 Zornitza Stark gene: DLG5 was added
gene: DLG5 was added to Renal ciliopathies. Sources: Literature
Mode of inheritance for gene: DLG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLG5 were set to 32631816
Phenotypes for gene: DLG5 were set to Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations
Review for gene: DLG5 was set to GREEN
gene: DLG5 was marked as current diagnostic
Added comment: Four unrelated families reported, supportive Xenopus animal model data. Mutlisystem ciliopathy with prominent renal features.
Sources: Literature
Intellectual disability v3.226 PJA1 Zornitza Stark reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Intellectual disability, trigonocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.226 SCAF4 Zornitza Stark reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32730804; Phenotypes: intellectual disability, seizures, behavioral abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Arthrogryposis v3.11 MYLPF Zornitza Stark gene: MYLPF was added
gene: MYLPF was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: MYLPF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLPF were set to 32707087
Phenotypes for gene: MYLPF were set to Distal arthrogryoposis
Review for gene: MYLPF was set to AMBER
Added comment: 2 different homozygous variants reported in 6 consanguineous families with DA and an additional 2 different dominantly inherited variants in 2 families, with supporting animal model. Overall neither MOI data sufficient for Green rating.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 NCKAP1L Zornitza Stark gene: NCKAP1L was added
gene: NCKAP1L was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: NCKAP1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCKAP1L were set to 32647003
Phenotypes for gene: NCKAP1L were set to Immunodeficiency; Immune dysregulation
gene: NCKAP1L was marked as current diagnostic
Added comment: 5 individuals from 4 families with recurrent bacterial and viral skin infections, severe respiratory tract infections leading to pneumonia and bronchiectasis. Functional studies of the 4 missense reported were performed.
Sources: Literature
Primary lymphoedema v2.4 FBXL7 Zornitza Stark gene: FBXL7 was added
gene: FBXL7 was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: FBXL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL7 were set to 31633297
Phenotypes for gene: FBXL7 were set to Hennekam syndrome; lymphoedema
Review for gene: FBXL7 was set to RED
Added comment: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mitochondrial disorders v2.8 HPDL Zornitza Stark gene: HPDL was added
gene: HPDL was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Leigh-like phenotype; progressive neurological disease
Review for gene: HPDL was set to GREEN
Added comment: Biallelic variants reported in 13 families with a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia. HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Suggest adding to ID panel and possibly others.
Sources: Literature
Retinal disorders v2.16 AHR Zornitza Stark reviewed gene: AHR: Rating: AMBER; Mode of pathogenicity: None; Publications: 29726989, 31896775; Phenotypes: Retinal dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.226 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.133 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Added comment: Comment on list classification: Currently, only half of reported cases present seizures which seem to follow after developmental concerns are apparent. Therefore rated Amber, awaiting further publications/clinical evidence to elucidate the contribution of EIF2AK2 variants to this phenotype.
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.132 EIF2AK2 Arina Puzriakova gene: EIF2AK2 was added
gene: EIF2AK2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877
Added comment: Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable).

PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect.
Sources: Literature
Inherited white matter disorders v1.82 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Green List (high evidence)
Inherited white matter disorders v1.82 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.81 EIF2AK2 Arina Puzriakova gene: EIF2AK2 was added
gene: EIF2AK2 was added to Inherited white matter disorders. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877
Review for gene: EIF2AK2 was set to GREEN
Added comment: Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable).

PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.8 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.8 EIF2AK2 Arina Puzriakova 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 v1.8 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.7 EIF2AK2 Arina Puzriakova gene: EIF2AK2 was added
gene: EIF2AK2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
for-review tags were added to gene: EIF2AK2.
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877
Review for gene: EIF2AK2 was set to GREEN
Added comment: Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable).

PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect.
Sources: Literature
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Amber List (moderate evidence)
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.226 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.225 EIF2AK2 Arina Puzriakova Tag for-review tag was added to gene: EIF2AK2.
Intellectual disability v3.225 EIF2AK2 Arina Puzriakova reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32197074; Phenotypes: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited white matter disorders v1.80 NDUFA2 Arina Puzriakova Tag watchlist was removed from gene: NDUFA2.
Inherited white matter disorders v1.80 NDUFA2 Arina Puzriakova Deleted their comment
Inherited white matter disorders v1.80 NDUFA2 Arina Puzriakova Classified gene: NDUFA2 as Green List (high evidence)
Inherited white matter disorders v1.80 NDUFA2 Arina Puzriakova Gene: ndufa2 has been classified as Green List (High Evidence).
Cholestasis v1.10 FARSB Arina Puzriakova Classified gene: FARSB as Amber List (moderate evidence)
Cholestasis v1.10 FARSB Arina Puzriakova Added comment: Comment on list classification: Gene has been added following suggestion for a GMS panel by the clinical team, but this is subject to review by the GMS specialist group, as not a clear match for this panel.
Cholestasis v1.10 FARSB Arina Puzriakova Gene: farsb has been classified as Amber List (Moderate Evidence).
Cholestasis v1.9 FARSB Arina Puzriakova gene: FARSB was added
gene: FARSB was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSB were set to 29573043; 29979980; 30014610
Phenotypes for gene: FARSB were set to Rajab interstitial lung disease with brain calcifications, 613658
Added comment: Associated with Rajab interstitial lung disease with brain calcifications in OMIM, but not in G2P.

Biallelic variants are associated with a multisystem disorder characterised by interstitial lung disease, cerebral aneurysms and brain calcifications, cirrhosis, and failure to thrive. At least six unrelated families described:

Antonellis et al. (2018) (PMID: 29573043) - Compound heterozygous variants (c.767C>T, p.Thr256Met; c.1486delCinsAA, p.His496Lysfs*14) identified in a male. Expression studies using patient fibroblasts showed severe depletion in protein levels, with indication of a loss-off-function effect.

Xu et al. 2018 (PMID: 29979980) - five affected individuals from four families with biallelic FARSB variants.

Zadjali et al. (2018) (PMID: 30014610) - eight affected individuals from a large consanguineous Omani family revealed homozygosity for a missense variant (c.853G>A, p.Glu285Lys).
Sources: Literature
Familial pulmonary fibrosis v1.11 FARSB Arina Puzriakova Classified gene: FARSB as Green List (high evidence)
Familial pulmonary fibrosis v1.11 FARSB Arina Puzriakova Added comment: Comment on list classification: Rating Green following consultation with the clinical team - sufficient number of cases with the relevant phenotype.
Familial pulmonary fibrosis v1.11 FARSB Arina Puzriakova Gene: farsb has been classified as Green List (High Evidence).
Familial pulmonary fibrosis v1.10 FARSB Arina Puzriakova gene: FARSB was added
gene: FARSB was added to Familial pulmonary fibrosis. Sources: Literature
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSB were set to 29573043; 29979980; 30014610
Phenotypes for gene: FARSB were set to Rajab interstitial lung disease with brain calcifications, 613658
Review for gene: FARSB was set to GREEN
Added comment: Associated with Rajab interstitial lung disease with brain calcifications in OMIM, but not in G2P.

Biallelic variants are associated with a multisystem disorder characterised by interstitial lung disease, cerebral aneurysms and brain calcifications, cirrhosis, and failure to thrive.

Antonellis et al. (2018) (PMID: 29573043) - Compound heterozygous variants (c.767C>T, p.Thr256Met; c.1486delCinsAA, p.His496Lysfs*14) identified in a male. Chest CT at 1.5 years and chest radiographs at 22 months, showed subpleural cystic changes in the bilateral lungs consistent with interstitial lung disease. Expression studies using patient fibroblasts showed severe depletion in protein levels, with indication of a loss-off-function effect.

Xu et al. 2018 (PMID: 29979980) - five affected individuals from four families with biallelic FARSB variants. All five participants described presented interstitial lung disease defined by cholesterol pneumonitis.

Zadjali et al. (2018) (PMID: 30014610) - eight affected individuals from a large consanguineous Omani family revealed homozygosity for a missense variant (c.853G>A, p.Glu285Lys). Respiratory failure and interstitial lung disease was a constant finding among affected individuals, with onset during the second decade of life.
Sources: Literature
Intracerebral calcification disorders v1.19 FARSB Arina Puzriakova Classified gene: FARSB as Green List (high evidence)
Intracerebral calcification disorders v1.19 FARSB Arina Puzriakova Added comment: Comment on list classification: Rating Green following consultation with the clinical team - sufficient number of cases with the relevant phenotype.
Intracerebral calcification disorders v1.19 FARSB Arina Puzriakova Gene: farsb has been classified as Green List (High Evidence).
Intracerebral calcification disorders v1.18 FARSB Arina Puzriakova reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573043, 29979980, 30014610; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.225 FARSB Arina Puzriakova Classified gene: FARSB as Amber List (moderate evidence)
Intellectual disability v3.225 FARSB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team in view of the inconsistent phenotype. Patients are more likely to be recognised on the basis of other phenotypic features, for which FARSB has been rated Green
Intellectual disability v3.225 FARSB Arina Puzriakova Gene: farsb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.224 FARSB Arina Puzriakova reviewed gene: FARSB: Rating: AMBER; Mode of pathogenicity: None; Publications: 29573043, 29979980, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications, 613658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.224 IREB2 Arina Puzriakova Tag watchlist tag was added to gene: IREB2.
Intellectual disability v3.224 IREB2 Arina Puzriakova Classified gene: IREB2 as Amber List (moderate evidence)
Intellectual disability v3.224 IREB2 Arina Puzriakova Added comment: Comment on list classification: Phenotype is appropriate for this panel, but additional cases necessary to support causation. Therefore rated Amber, awaiting further publications/clinical evidence (added to watchlist).
Intellectual disability v3.224 IREB2 Arina Puzriakova Gene: ireb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.223 IREB2 Arina Puzriakova reviewed gene: IREB2: Rating: ; Mode of pathogenicity: None; Publications: 30915432, 31243445; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.223 CHD1 Arina Puzriakova changed review comment from: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

Pilarowski et al (2018) (PMID: 28866611) reported heterozygous missense variants in five individuals (two sibs and three singletons) as the cause of developmental delay, speech apraxia, hypotonia, and facial dysmorphic features. Two variants were confirmed de novo, while segregation for others could not be determined (including the two sibs who were conceived by egg donor). Developmental delay was noted for all participants; however, ID was only reported in the two sibs.; to: Gene is associated with Pilarowski-Bjornsson syndrome in OMIM, but not in G2P.

Pilarowski et al (2018) (PMID: 28866611) reported heterozygous missense variants in five individuals (two sibs and three singletons) as the cause of developmental delay, speech apraxia, hypotonia, and facial dysmorphic features. Two variants were confirmed de novo, while segregation for others could not be determined (including the two sibs who were conceived by egg donor). Developmental delay was noted for all participants; however, ID was only reported in the two sibs. Further insight may be gained from re-evaluation of the two patients in the present study who were too young for a formal neurocognitive evaluation at the time of publication.
Intellectual disability v3.223 CHD1 Arina Puzriakova Classified gene: CHD1 as Amber List (moderate evidence)
Intellectual disability v3.223 CHD1 Arina Puzriakova Added comment: Comment on list classification: Phenotype is appropriate for the panel, but insufficient cases to support causation (ID only reported in two sibs). Therefore rated Amber, awaiting further publications/clinical evidence.
Intellectual disability v3.223 CHD1 Arina Puzriakova Gene: chd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.222 CHD1 Arina Puzriakova reviewed gene: CHD1: Rating: ; Mode of pathogenicity: None; Publications: 28866611; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.222 PAM16 Arina Puzriakova Tag founder-effect tag was added to gene: PAM16.
Intellectual disability v3.222 PAM16 Arina Puzriakova Classified gene: PAM16 as Amber List (moderate evidence)
Intellectual disability v3.222 PAM16 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases, but two share the same founder mutation - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.222 PAM16 Arina Puzriakova Gene: pam16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.221 PAM16 Arina Puzriakova Tag watchlist tag was added to gene: PAM16.
Intellectual disability v3.221 PAM16 Arina Puzriakova reviewed gene: PAM16: Rating: ; Mode of pathogenicity: None; Publications: 24786642, 27354339; Phenotypes: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, 613320; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.6 NDUFA2 Arina Puzriakova Classified gene: NDUFA2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.6 NDUFA2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least three unrelated cases presenting a movement phenotype following a period of regression.
Dystonia, chorea or related movement disorder, childhood onset v1.6 NDUFA2 Arina Puzriakova Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.5 NDUFA2 Arina Puzriakova Tag for-review tag was added to gene: NDUFA2.
Dystonia, chorea or related movement disorder, childhood onset v1.5 NDUFA2 Arina Puzriakova edited their review of gene: NDUFA2: Changed rating: GREEN
Intellectual disability v3.221 NDUFA2 Arina Puzriakova Classified gene: NDUFA2 as Amber List (moderate evidence)
Intellectual disability v3.221 NDUFA2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least four unrelated cases reported with DD/ID, mostly following a period of regression.
Intellectual disability v3.221 NDUFA2 Arina Puzriakova Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.220 NDUFA2 Arina Puzriakova Tag watchlist was removed from gene: NDUFA2.
Tag for-review tag was added to gene: NDUFA2.
Intellectual disability v3.220 NDUFA2 Arina Puzriakova Tag watchlist tag was added to gene: NDUFA2.
Intellectual disability v3.220 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.5 NDUFA2 Arina Puzriakova Classified gene: NDUFA2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.5 NDUFA2 Arina Puzriakova Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.4 NDUFA2 Arina Puzriakova Tag watchlist was removed from gene: NDUFA2.
Dystonia, chorea or related movement disorder, childhood onset v1.4 NDUFA2 Arina Puzriakova Tag watchlist tag was added to gene: NDUFA2.
Dystonia, chorea or related movement disorder, childhood onset v1.4 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.131 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: ; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.79 NDUFA2 Arina Puzriakova Classified gene: NDUFA2 as Amber List (moderate evidence)
Inherited white matter disorders v1.79 NDUFA2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Inherited white matter disorders v1.79 NDUFA2 Arina Puzriakova Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Inherited white matter disorders v1.78 NDUFA2 Arina Puzriakova Tag watchlist tag was added to gene: NDUFA2.
Inherited white matter disorders v1.78 NDUFA2 Arina Puzriakova edited their review of gene: NDUFA2: Changed rating: GREEN
Inherited white matter disorders v1.78 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: ; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.74 CALCRL Zornitza Stark gene: CALCRL was added
gene: CALCRL was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CALCRL were set to 30115739
Phenotypes for gene: CALCRL were set to Lymphatic malformation 8 (MIM# 618773); hydrops fetalis
Review for gene: CALCRL was set to RED
Added comment: Single family reported with several affected pregnancies.
Sources: Literature
Malformations of cortical development v2.7 MCF2 Zornitza Stark gene: MCF2 was added
gene: MCF2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: MCF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MCF2 were set to 31846234
Phenotypes for gene: MCF2 were set to Perisylvian polymicrogyria
Review for gene: MCF2 was set to RED
Added comment: Single individual reported, inherited missense variant from unaffected mother, some support from mouse model.
Sources: Literature
Fetal anomalies v1.74 AMBRA1 Zornitza Stark gene: AMBRA1 was added
gene: AMBRA1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: AMBRA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMBRA1 were set to 17589504; 32333458
Phenotypes for gene: AMBRA1 were set to Neural tube defects
Review for gene: AMBRA1 was set to GREEN
gene: AMBRA1 was marked as current diagnostic
Added comment: 5 rare missense variants were identified in 6 cases from a neural tube defect cohort, and 4 (p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) of them were functionally validated to affect autophagy regulation in vitro or zebrafish embryo development in vivo. There is also null mouse model with neural tube defects.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 IVNS1ABP Zornitza Stark reviewed gene: IVNS1ABP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32499645; Phenotypes: Immunodeficiency 70, MIM#618969; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 PTPN2 Zornitza Stark gene: PTPN2 was added
gene: PTPN2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PTPN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN2 were set to 32499645; 27658548
Phenotypes for gene: PTPN2 were set to Lupus; arthritis; common variable immunodeficiency
Review for gene: PTPN2 was set to AMBER
Added comment: A single family with a proband diagnosed with CVID and arthiritis (among other features) with an intronic expression quantitative trait loci (eQTL) rs2847297-G in trans with a stopgain variant. The stopgain variant was also identified in the proband's mother, who was diagnosed with lupus. A Ptpn2 deficient mouse model also demonstrates an autoimmune phenotype.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 SOCS1 Zornitza Stark gene: SOCS1 was added
gene: SOCS1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SOCS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOCS1 were set to 32499645; 10490099; 10490100
Phenotypes for gene: SOCS1 were set to Common variable immunodeficiency
Review for gene: SOCS1 was set to GREEN
gene: SOCS1 was marked as current diagnostic
Added comment: 2 unrealted families with truncating variants with supportive immunophenotyping of patient cells, and supporting null mouse models.
Sources: Literature
Gastrointestinal epithelial barrier disorders v1.59 ANO1 Zornitza Stark gene: ANO1 was added
gene: ANO1 was added to Gastrointestinal epithelial barrier disorders. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Phenotypes for gene: ANO1 were set to Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features
Review for gene: ANO1 was set to AMBER
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Skeletal dysplasia v2.11 PLCB3 Zornitza Stark gene: PLCB3 was added
gene: PLCB3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PLCB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCB3 were set to 29122926
Phenotypes for gene: PLCB3 were set to Spondylometaphyseal dysplasia with corneal dystrophy, MIM# 618961
Review for gene: PLCB3 was set to RED
Added comment: Single consanguineous family reported.
Sources: Literature
Hereditary neuropathy or pain disorder v1.6 ACOX1 Zornitza Stark gene: ACOX1 was added
gene: ACOX1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: ACOX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACOX1 were set to 32169171
Phenotypes for gene: ACOX1 were set to Mitchell syndrome, MIM# 618960
Review for gene: ACOX1 was set to GREEN
gene: ACOX1 was marked as current diagnostic
Added comment: Mono-allelic variants (recurrent de novo missense, N237S) associated with Mitchell syndrome (MITCH): a progressive disorder characterised by episodic demyelination, sensorimotor polyneuropathy, and hearing loss. By contrast, bi-allelic variants cause a peroxisomal disorder characterised by neonatal hypotonia, seizures, apnoeic spells, delayed psychomotor development, and neurologic regression.
Sources: Literature
Intellectual disability v3.220 NDUFAF1 Arina Puzriakova Classified gene: NDUFAF1 as Amber List (moderate evidence)
Intellectual disability v3.220 NDUFAF1 Arina Puzriakova Added comment: Comment on list classification: Additional case of ID required before inclusion of NDUFAF1 on a diagnostic panel (added to watchlist).
Intellectual disability v3.220 NDUFAF1 Arina Puzriakova Gene: ndufaf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.219 NDUFAF1 Arina Puzriakova Tag watchlist tag was added to gene: NDUFAF1.
Intellectual disability v3.219 NDUFAF1 Arina Puzriakova reviewed gene: NDUFAF1: Rating: ; Mode of pathogenicity: None; Publications: 17557076, 21931170, 24963768; Phenotypes: Mitochondrial complex I deficiency, nuclear type 11, 618234; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arrhythmogenic right ventricular cardiomyopathy v2.6 CDH2 Zornitza Stark reviewed gene: CDH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia, familial, 14, OMIM#618920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arrhythmogenic right ventricular cardiomyopathy v2.6 RYR2 Zornitza Stark reviewed gene: RYR2: Rating: RED; Mode of pathogenicity: None; Publications: 11159936, 25041964, 29543670; Phenotypes: Arrhythmogenic right ventricular dysplasia 2, MIM# 600996; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.219 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Early onset or syndromic epilepsy v2.131 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Early onset or syndromic epilepsy v2.131 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability v3.219 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability v3.219 ZNF407 Konstantinos Varvagiannis gene: ZNF407 was added
gene: ZNF407 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF407 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZNF407 were set to 24907849; 32737394; 23195952
Phenotypes for gene: ZNF407 were set to Global developmental delay; Intellectual disability
Penetrance for gene: ZNF407 were set to unknown
Review for gene: ZNF407 was set to AMBER
Added comment: You may consider inclusion of this gene probably with amber rating (or green if the evidence for biallelic variants is considered sufficient).

Biallelic variants:

- Kambouris et al. (2014 - PMID: 24907849) described 2 brothers with severe DD and ID, born to first cousin parents. Homozygosity mapping, following other non-diagnostic investigations (incl. aCGH), revealed 4 major homozygosity intervals. Exome sequencing in one identified 5 variants within these intervals, ZNF407 (c.5054C>G, p.Ser1685Trp) being the best candidate, supported also by segregation studies. The authors commented that zinc finger proteins act as transcriptional regulators, with mutations in genes encoding for other zinc finger proteins interfering with normal brain development.

- Zahra et al. (2020 - PMID: 32737394) report on 7 affected individuals (from 3 families) homozygous or compound heterozygous for ZNF407 variants. Features included hypotonia, DD and ID (in all) and variable occurrence of short stature (6/6), microcephaly (in at least 5), behavioural, visual problems and deafness. Linkage analysis in the first family revealed a 4.4 Mb shared homozygosity region and exome (30x) revealed a 3-bp duplication, confirmed by Sanger sequencing and segregating with the disease (NM_001146189:c.2814_2816dup, p.Val939dup). Affected subjects from the 2 other families were each found to be homozygous (c.2405G>T) or compound heterozygous (c.2884C>G, c.3642G>C) for other variants. Segregation was compatible in all families. Other studies were not performed. The authors comment than only the 3-bp duplication fulfilled ACMG criteria for classification as LP, the other variants being all formally classified as VUS (also due to in silico predictions predicting a LB effect). In addition, while several features such as DD/ID and short stature appeared to be frequent among all patients reported, Zahra et all comment that there was partial clinical overlap with the sibs described by Kambouris et al (additional variants?).


Monoallelic disruption of ZNF407:

- Ren et al (2013 - PMID: 23195952) described an 8 y.o. boy with ID and ASD. The boy was found to harbor a de novo translocation between chromosomes 3 and 18 [46,XY,t(3;18)(p13;q22.3)]. Array CGH did not reveal any P/LP CNV. Delineation of the breakpoints (FISH, long-range PCR) revealed that the chr18 breakpoint disrupted intron 3 of ZNF407 (isoform 1) with the other breakpoint within a gene-free region of exon 3. There was a loss of 4-8 nt in chr18 and 2-6 in chr3. Sequencing of ZNF407 did not reveal additional variants. RNA isolation in blood followed by RT-PCR studied expression of all 3 ZNF407 isoforms (the intronic region being shared by isoforms 1 and 2). Expression of isoform 1 was shown to be significantly reduced compared to controls. Isoform 2 was undetectable (in blood) while isoform 3 expression was similar to controls. Sequencing of 105 additional patients with similar clinical presentation (ID & ASD) revealed 2 further individuals with de novo missense variants.

- Based on the discussion by Kambouris et al (PMID: 24907849 - cited literature not here reviewed) ZNF407 may be deleted in patients with congenital aural atresia due to deletion of a critical region of 18q22.3 (though TSHZ1 is responsible for this phenotype) or 18q- although such deletions span several other genes (cited PMID: 16639285). In one case the breakpoint was shown to be disrupting ZNF407 (cited PMID: 24092497).

- The denovo db and Decipher (research variant tab) list few individuals with de novo ZNF407 SNVs although these do not seem to allow conclusions.

https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF407
https://decipher.sanger.ac.uk/search/ddd-research-variants/results?q=znf407
Sources: Literature
Glaucoma (developmental) v1.8 OCRL Zornitza Stark gene: OCRL was added
gene: OCRL was added to Glaucoma (developmental). Sources: Expert list
Mode of inheritance for gene: OCRL was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: OCRL were set to Lowe syndrome, MIM# 309000
Review for gene: OCRL was set to GREEN
gene: OCRL was marked as current diagnostic
Added comment: Glaucoma present in ~50%, GeneReviews.
Sources: Expert list
Glaucoma (developmental) v1.8 IFIH1 Zornitza Stark gene: IFIH1 was added
gene: IFIH1 was added to Glaucoma (developmental). Sources: Expert list
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IFIH1 were set to Singleton-Merten syndrome 1, MIM# 182250
Review for gene: IFIH1 was set to GREEN
gene: IFIH1 was marked as current diagnostic
Added comment: Glaucoma is a feature of this condition.
Sources: Expert list
Glaucoma (developmental) v1.8 TEK Zornitza Stark gene: TEK was added
gene: TEK was added to Glaucoma (developmental). Sources: Expert list
Mode of inheritance for gene: TEK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TEK were set to 27270174
Phenotypes for gene: TEK were set to Glaucoma 3, primary congenital, E, MIM# 617272
Review for gene: TEK was set to GREEN
gene: TEK was marked as current diagnostic
Added comment: Ten families and a supportive mouse model.
Sources: Expert list
Glaucoma (developmental) v1.8 CREBBP Zornitza Stark gene: CREBBP was added
gene: CREBBP was added to Glaucoma (developmental). Sources: Expert list
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CREBBP were set to Rubinstein Taybi syndrome
Review for gene: CREBBP was set to GREEN
gene: CREBBP was marked as current diagnostic
Added comment: Glaucoma is a feature of this syndrome.
Sources: Expert list
Glaucoma (developmental) v1.8 SH3PXD2B Zornitza Stark edited their review of gene: SH3PXD2B: Set current diagnostic: yes
Glaucoma (developmental) v1.8 SH3PXD2B Zornitza Stark gene: SH3PXD2B was added
gene: SH3PXD2B was added to Glaucoma (developmental). Sources: Expert list
Mode of inheritance for gene: SH3PXD2B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SH3PXD2B were set to Frank-ter Haar syndrome, MIM# 249420
Review for gene: SH3PXD2B was set to GREEN
Added comment: Glaucoma is part of the phenotype.
Sources: Expert list
Glaucoma (developmental) v1.8 SBF2 Zornitza Stark reviewed gene: SBF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12687498, 15304601; Phenotypes: Charcot-Marie-Tooth disease, type 4B2, MIM# 604563; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Glaucoma (developmental) v1.8 PAX6 Zornitza Stark reviewed gene: PAX6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Anterior segment dysgenesis 5, multiple subtypes, MIM# 604229; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Glaucoma (developmental) v1.8 LMX1B Zornitza Stark gene: LMX1B was added
gene: LMX1B was added to Glaucoma (developmental). Sources: Expert list
Mode of inheritance for gene: LMX1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LMX1B were set to Nail-patella syndrome, MIM# 161200
Review for gene: LMX1B was set to GREEN
Added comment: Glaucoma is a key feature of this condition.
Sources: Expert list
Glaucoma (developmental) v1.8 FOXD3 Zornitza Stark reviewed gene: FOXD3: Rating: RED; Mode of pathogenicity: None; Publications: 22815627; Phenotypes: Anterior segment dysgenesis, Peters anomaly, Glaucoma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood solid tumours cancer susceptibility v1.6 TRIP13 Zornitza Stark changed review comment from: Predisposition to Wilms tumour.; to: Predisposition to Wilms tumour, six unrelated individuals reported.
Childhood solid tumours cancer susceptibility v1.6 TRIP13 Zornitza Stark edited their review of gene: TRIP13: Changed publications: 28553959
Childhood solid tumours cancer susceptibility v1.6 TRIP13 Zornitza Stark reviewed gene: TRIP13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mosaic variegated aneuploidy syndrome 3, MIM# 617598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood solid tumours cancer susceptibility v1.6 NOP10 Zornitza Stark reviewed gene: NOP10: Rating: RED; Mode of pathogenicity: None; Publications: 17507419; Phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood solid tumours cancer susceptibility v1.6 HRAS Zornitza Stark reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Costello syndrome, MIM# 218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood solid tumours cancer susceptibility v1.6 DIS3L2 Zornitza Stark reviewed gene: DIS3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Perlman syndrome, MIM# 267000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood solid tumours cancer susceptibility v1.6 BUB1B Zornitza Stark reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31081598, 31053147; Phenotypes: Mosaic variegated aneuploidy syndrome 1, MIM# 257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.219 MAPK1 Konstantinos Varvagiannis gene: MAPK1 was added
gene: MAPK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Penetrance for gene: MAPK1 were set to unknown
Mode of pathogenicity for gene: MAPK1 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: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).

The authors comment that screening of 267 additional individuals with suspected RASopathy (without mutations in previously implicated genes) did not reveal other MAPK1 variants.

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Intellectual disability v3.219 NCAPH Arina Puzriakova Classified gene: NCAPH as Red List (low evidence)
Intellectual disability v3.219 NCAPH Arina Puzriakova Added comment: Comment on list classification: Additional cases are required to substantiate causation but added to watchlist.
Intellectual disability v3.219 NCAPH Arina Puzriakova Gene: ncaph has been classified as Red List (Low Evidence).
Intellectual disability v3.218 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: NCAPH.
Mode of inheritance for gene: NCAPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPH were set to 27737959
Phenotypes for gene: NCAPH were set to Microcephaly 23, primary, autosomal recessive, 617985
Added comment: Associated with Microcephaly 23 in OMIM and a possible gene for microcephaly in G2P.

PMID: 27737959 (2016) - A homozygous missense variant in NCAPH (c.728C>T, p.Pro243Leu) was detected in a 42-year-old male with microcephaly (OFC -4.2 SD) and moderate ID. Functional studies indicated that although the variant did not affect cellular protein levels, it disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature
Severe microcephaly v2.17 NCAPH Arina Puzriakova Tag watchlist tag was added to gene: NCAPH.
Severe microcephaly v2.17 NCAPH Arina Puzriakova Classified gene: NCAPH as Red List (low evidence)
Severe microcephaly v2.17 NCAPH Arina Puzriakova Added comment: Comment on list classification: Additional cases are required to substantiate causation but added to watchlist.
Severe microcephaly v2.17 NCAPH Arina Puzriakova Gene: ncaph has been classified as Red List (Low Evidence).
Severe microcephaly v2.16 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NCAPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPH were set to 27737959
Phenotypes for gene: NCAPH were set to Microcephaly 23, primary, autosomal recessive, 617985
Added comment: Associated with Microcephaly 23 in OMIM and a possible gene for microcephaly in G2P.

PMID: 27737959 (2016) - A homozygous missense variant in NCAPH (c.728C>T, p.Pro243Leu) was detected in a 42-year-old male with microcephaly (OFC -4.2 SD) and moderate ID. Functional studies indicated that although the variant did not affect cellular protein levels, it disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature
Severe microcephaly v2.15 NCAPD3 Arina Puzriakova Classified gene: NCAPD3 as Amber List (moderate evidence)
Severe microcephaly v2.15 NCAPD3 Arina Puzriakova Added comment: Comment on list classification: Additional cases, as well as a more significant pattern of microcephaly, are required before inclusion of NCAPD3 on a diagnostic panel.
Severe microcephaly v2.15 NCAPD3 Arina Puzriakova Gene: ncapd3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.14 NCAPD3 Arina Puzriakova gene: NCAPD3 was added
gene: NCAPD3 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NCAPD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD3 were set to 27737959
Phenotypes for gene: NCAPD3 were set to Microcephaly 22, primary, autosomal recessive, 617984
Review for gene: NCAPD3 was set to AMBER
Added comment: Associated with Microcephaly 22 in OMIM and a possible gene for Microcephaly with short stature in G2P.

PMID: 27737959 (2016) - Two unrelated cases. Compound heterozygous variants ([c.1783_1784delG, p.Val595Serfs*34];[c.382+14A>G, p.Ser129Metfs*1]) were detected in a 6-years-5-month-old male with microcephaly (OFC -5.4 SD). The second patient (aged 6-years-11-months-old) was less severely microcephalic (OFC -2.7 SD) but additionally had moderate developmental delay, seizures and lower limb hypertonia, and also harboured a homozygous missense variant in NCAPD3 (c.3458T>G, p.Glu1153Ala).

Functional studies indicated that both variants disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Classified gene: NCAPG2 as Amber List (moderate evidence)
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Added comment: Comment on list classification: Additional cases required to ascertain the contribution of NCAPG2 variants to an ID phenotype.
Intellectual disability v3.217 NCAPG2 Arina Puzriakova Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.216 NCAPG2 Arina Puzriakova reviewed gene: NCAPG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30609410; Phenotypes: Khan-Khan-Katsanis syndrome, 618460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Tag for-review tag was added to gene: NCAPD2.
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Classified gene: NCAPD2 as Amber List (moderate evidence)
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least three unrelated pedigrees with the relevant phenotype.
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Gene: ncapd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.12 NCAPD2 Arina Puzriakova gene: NCAPD2 was added
gene: NCAPD2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD2 were set to 27737959; 28097321; 31056748
Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive, 617983
Review for gene: NCAPD2 was set to GREEN
Added comment: Associated with phenotype in OMIM and a possible gene for Microcephaly with short stature in G2P.

PMID: 27737959 (2016) - A homozygous splice site variant (c.4120+2T>C, p.Asp1374Glyfs*29) in NCAPD2 was detected in a 3-year-old male with severe microcephaly (OFC -11.9 SD), severe ID, autistic-like behaviours, and no speech. The variant was found in a heterozygous state in both unaffected parents and was not present in the ExAC database. Functional studies indicated that the variant disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity.

PMID: 28097321 (2017) - In two affected cousins from a consanguineous family with mild ID, intrauterine growth retardation, short stature, and microcephaly. Homozygous missense variants were found in NCAPD2 (c.23T>C, p.Phe8Ser), but also in ENO2 (c.710C>T, p.Thr237Met). Variants segregated with disease in the family, but no further functional studies were undertaken of the variants or patient cells.

PMID: 31056748 (2019) - In a 13-year-old female with severe microcephaly (OFC < -3), mild ID (IQ 59), poor learning performance, sloping forehead and reduced cerebral cortex size, exome sequencing revealed a homozygous variant in NCAPD2 (c.3477+2T>C, p.Gly1160Valfs*16). Progressive microcephaly was also apparent in a sibling of the proband, a male fetus which was terminated at 34 weeks of pregnancy. The same homozygous variant was identified in the fetus, while parents were heterozygotes and an unaffected brother was homozygous for the other allele. No further functional studies of the variant or patient cells were performed.
Sources: Literature
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Tag watchlist tag was added to gene: NCAPD2.
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Classified gene: NCAPD2 as Amber List (moderate evidence)
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Added comment: Comment on list classification: Amber rating as only one patient has been described with severe ID. However, added to watchlist in case of new reports of more significant cases of ID. Gene has also been added with a Green rating on the Severe Microcephaly panel.
Intellectual disability v3.216 NCAPD2 Arina Puzriakova Gene: ncapd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.215 NCAPD2 Arina Puzriakova reviewed gene: NCAPD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27737959, 28097321, 31056748; Phenotypes: Microcephaly 21, primary, autosomal recessive, 617983; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.215 HADHB Arina Puzriakova Classified gene: HADHB as Amber List (moderate evidence)
Intellectual disability v3.215 HADHB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the clinical team, in view of the borderline ID phenotype. Cases are more likely to be recognised on the basis of the metabolic phenotype, for which this gene is Green already.
Intellectual disability v3.215 HADHB Arina Puzriakova Gene: hadhb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.214 HADHB Arina Puzriakova reviewed gene: HADHB: Rating: AMBER; Mode of pathogenicity: None; Publications: 12754706, 19699128; Phenotypes: Trifunctional protein deficiency, 609015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.26 IFT27 Arina Puzriakova Tag for-review tag was added to gene: IFT27.
Limb disorders v2.13 IFT27 Arina Puzriakova Tag for-review tag was added to gene: IFT27.
Intellectual disability v3.214 MN1 Arina Puzriakova Tag for-review tag was added to gene: MN1.
Intellectual disability v3.214 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Intellectual disability v3.214 MN1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.214 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.213 VPS51 Arina Puzriakova Classified gene: VPS51 as Amber List (moderate evidence)
Intellectual disability v3.213 VPS51 Arina Puzriakova Added comment: Comment on list classification: Additional cases are required before inclusion of VPS51 on a diagnostic panel; however, gene added to watchlist.
Intellectual disability v3.213 VPS51 Arina Puzriakova Gene: vps51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.212 VPS51 Arina Puzriakova reviewed gene: VPS51: Rating: AMBER; Mode of pathogenicity: None; Publications: 30624672, 31207318; Phenotypes: Pontocerebellar hypoplasia, type 13, 618606; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.212 LRRC32 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P.

PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months).

Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation.; to: Not associated with phenotype in OMIM or G2P.

PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months).

Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation (added founder-effect tag).
Intellectual disability v3.212 LRRC32 Arina Puzriakova Tag founder-effect tag was added to gene: LRRC32.
Intellectual disability v3.212 LRRC32 Arina Puzriakova Classified gene: LRRC32 as Red List (low evidence)
Intellectual disability v3.212 LRRC32 Arina Puzriakova Added comment: Comment on list classification: Rated Red as there is not currently enough evidence that other variants in the LRRC32 gene are disease causing.
Intellectual disability v3.212 LRRC32 Arina Puzriakova Gene: lrrc32 has been classified as Red List (Low Evidence).
Intellectual disability v3.211 LRRC32 Arina Puzriakova reviewed gene: LRRC32: Rating: RED; Mode of pathogenicity: None; Publications: 30976112; Phenotypes: Global developmental delay, Speech delay, Hypotonia, Cleft palate, Proliferative retinopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.131 LMAN2L Arina Puzriakova Classified gene: LMAN2L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.131 LMAN2L Arina Puzriakova Gene: lman2l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.130 LMAN2L Arina Puzriakova gene: LMAN2L was added
gene: LMAN2L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMAN2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMAN2L were set to 31020005; 26566883
Phenotypes for gene: LMAN2L were set to Intellectual disability; Epilepsy
Review for gene: LMAN2L was set to AMBER
Added comment: PMID: 26566883 (2015) - One consanguineous family with 7 individuals with ID and epilepsy. Five individuals presented mild epileptic seizures in the first year of life, until the age of 5 years when seizures stopped spontaneously without any medication. Typical seizure episodes lasted for 3 to 5 min. Epilepsy was also reported in two other family members, who died at the age of 7 and 16 years and therefore could not be included in the study. A homozygous LMAN2L missense variant (c.158 G>A, p.R53Q) segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies.

PMID: 31020005 (2019) - One non-consanguineous family with 4 affected, harbouring a heterozygous frameshift LMAN2L variant (c.1073delT, p.Phe358Serfs*16) which segregated with disease in the family. All suffered generalised tonic‐clonic seizures in childhood, however all had undergone remission with normalized EEG by adolescence. Functional studies show the variant eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane.
Sources: Literature
Intellectual disability v3.211 LMAN2L Arina Puzriakova Classified gene: LMAN2L as Amber List (moderate evidence)
Intellectual disability v3.211 LMAN2L Arina Puzriakova Added comment: Comment on list classification: Two families with ID phenotype (one mild, one severe). Amber rating as additional cases and functional data are required to validate the causal association with the phenotype.
Intellectual disability v3.211 LMAN2L Arina Puzriakova Gene: lman2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.210 LMAN2L Arina Puzriakova Tag watchlist tag was added to gene: LMAN2L.
Intellectual disability v3.210 LAMB2 Arina Puzriakova Classified gene: LAMB2 as Amber List (moderate evidence)
Intellectual disability v3.210 LAMB2 Arina Puzriakova Added comment: Comment on list classification: Given the incomplete penetrance of the ID phenotype, these patients are more likely to be recognised on the basis of the renal phenotype and ocular abnormalilites - LAMB2 has a Green rating on these panels, while an Amber classification might be most appropriate for the ID panel.
Intellectual disability v3.210 LAMB2 Arina Puzriakova Gene: lamb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.209 LAMB2 Arina Puzriakova reviewed gene: LAMB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 15367484, 17256789; Phenotypes: Pierson syndrome, 609049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.13 IFT27 Arina Puzriakova Publications for gene: IFT27 were set to 24488770; 29704304
Limb disorders v2.12 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Limb disorders v2.12 IFT27 Arina Puzriakova Added comment: Comment on list classification: With the addition of recent publications, there are now at least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.
Limb disorders v2.12 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.11 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.26 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Renal ciliopathies v1.26 IFT27 Arina Puzriakova Added comment: Comment on list classification: With the addition of the recent publication, there are now at least three unrelated cases reported with a renal phenotype, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.
Renal ciliopathies v1.26 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.25 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.6 IFT27 Arina Puzriakova Publications for gene: IFT27 were set to
Ophthalmological ciliopathies v1.5 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.5 IFT27 Arina Puzriakova Added comment: Comment on list classification: With the addition of recent publications, there are now at least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.
Ophthalmological ciliopathies v1.5 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.4 IFT27 Arina Puzriakova Tag for-review tag was added to gene: IFT27.
Ophthalmological ciliopathies v1.4 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare multisystem ciliopathy disorders v1.127 IFT27 Arina Puzriakova Publications for gene: IFT27 were set to
Rare multisystem ciliopathy disorders v1.126 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Rare multisystem ciliopathy disorders v1.126 IFT27 Arina Puzriakova Added comment: Comment on list classification: With the addition of recent publications, there are now at least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.
Rare multisystem ciliopathy disorders v1.126 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Rare multisystem ciliopathy disorders v1.125 IFT27 Arina Puzriakova Tag for-review tag was added to gene: IFT27.
Rare multisystem ciliopathy disorders v1.125 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.16 IFT27 Arina Puzriakova Mode of inheritance for gene: IFT27 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.15 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Retinal disorders v2.15 IFT27 Arina Puzriakova Added comment: Comment on list classification: At least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.
Retinal disorders v2.15 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.14 IFT27 Arina Puzriakova Tag for-review tag was added to gene: IFT27.
Retinal disorders v2.14 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 24488770, 29704304, 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bardet Biedl syndrome v1.5 IFT27 Arina Puzriakova Publications for gene: IFT27 were set to 24488770
Bardet Biedl syndrome v1.4 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Bardet Biedl syndrome v1.4 IFT27 Arina Puzriakova Added comment: Comment on list classification: With the addition of recent publications, there are now at least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.
Bardet Biedl syndrome v1.4 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v1.3 IFT27 Arina Puzriakova Tag for-review tag was added to gene: IFT27.
Bardet Biedl syndrome v1.3 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.209 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.7 TUBB2A Arina Puzriakova edited their review of gene: TUBB2A: Changed publications: 32571897
Early onset or syndromic epilepsy v2.129 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.7 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy v1.374 PMP22 Eleanor Williams reviewed gene: PMP22: Rating: ; Mode of pathogenicity: None; Publications: 32356557; Phenotypes: ; Mode of inheritance: None
Structural eye disease v1.9 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.14 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Congenital hypothyroidism v2.3 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Anophthalmia or microphthalmia v1.25 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Ocular coloboma v1.36 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.74 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.4 OTX2 Eleanor Williams reviewed gene: OTX2: Rating: ; Mode of pathogenicity: None; Publications: 32277752; Phenotypes: ; Mode of inheritance: None
Rare anaemia v1.4 CDAN1 Arina Puzriakova reviewed gene: CDAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32518175; Phenotypes: Dyserythropoietic anemia, congenital, type Ia, 224120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenias and congenital anaemias v1.73 CDAN1 Arina Puzriakova reviewed gene: CDAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32518175; Phenotypes: Dyserythropoietic anemia, congenital, type Ia, 224120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.15 NGLY1 Eleanor Williams reviewed gene: NGLY1: Rating: ; Mode of pathogenicity: None; Publications: 32259258; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.209 NGLY1 Eleanor Williams reviewed gene: NGLY1: Rating: ; Mode of pathogenicity: None; Publications: 32259258; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.4 NGLY1 Eleanor Williams reviewed gene: NGLY1: Rating: ; Mode of pathogenicity: None; Publications: 32259258; Phenotypes: ; Mode of inheritance: None
Congenital disorders of glycosylation v2.14 NGLY1 Eleanor Williams reviewed gene: NGLY1: Rating: ; Mode of pathogenicity: None; Publications: 32259258; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v2.11 GNPNAT1 Arina Puzriakova Classified gene: GNPNAT1 as Amber List (moderate evidence)
Skeletal dysplasia v2.11 GNPNAT1 Arina Puzriakova Added comment: Comment on list classification: Amber rating as only one family, but some supporting functional data. Additional cases required to validate pathogenicity of GNPNAT1.
Skeletal dysplasia v2.11 GNPNAT1 Arina Puzriakova Gene: gnpnat1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova edited their review of gene: GNPNAT1: Changed rating: AMBER
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova changed review comment from: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1.
Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature
Early onset or syndromic epilepsy v2.129 SETD1B Arina Puzriakova reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.209 SETD1B Arina Puzriakova reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pancreatitis v2.4 TRPV6 Miranda Durkie gene: TRPV6 was added
gene: TRPV6 was added to Pancreatitis. Sources: Literature
Mode of inheritance for gene: TRPV6 was set to Unknown
Publications for gene: TRPV6 were set to PMID: 31930989; 32383311
Phenotypes for gene: TRPV6 were set to Chronic pancreatitis
Penetrance for gene: TRPV6 were set to unknown
Review for gene: TRPV6 was set to AMBER
Added comment: PMID: 31930989: Heterozygous variants that affected function of the TRPV6 protein statistically over represented in cases vs controls (300 cases from Japan, 470 from France, 410 from Germany & >1000 controls). Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P ¼ 2.4 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P ¼ 6.2 10–8). Homozygous mouse model given cerulein developed more severe pancreatitis than control mice (although homozygous / compound heterozygous disease in humans associated with transient neonatal hyperparathyroidism (OMIM 618188) with no reported pancreatitis). Also reported 20% had trans-heterozygous SPINK1 pathogenic variants.
PMID: 32383311: Chinese case control study of 669 cases and 609 controls showed over represented of confirmed loss of function alleles (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022).
Hypothesised treatment with Vitamin D may be beneficial.
Likely susceptibility allele therefore amber rating currently
Sources: Literature
Retinal disorders v2.14 IMPG2 Eleanor Williams changed review comment from: PMID: 32242237 - Xu et al 2020 - created two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique. Impg2 ablation in mice recapitulated the retinitis pigmentosa phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The study looks at the effects of Impg2 KO in retinas in detail and provides novel models for mechanistic investigations and development of therapies.; to: Additional evidence for association with retinitis pigmentosa - PMID: 32242237 - Xu et al 2020 - created two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique. Impg2 ablation in mice recapitulated the retinitis pigmentosa phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The study looks at the effects of Impg2 KO in retinas in detail and provides novel models for mechanistic investigations and development of therapies.
Retinal disorders v2.14 IMPG2 Eleanor Williams reviewed gene: IMPG2: Rating: ; Mode of pathogenicity: None; Publications: 32242237; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova changed review comment from: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1.
Sources: Literature
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova gene: GNPNAT1 was added
gene: GNPNAT1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNPNAT1 were set to 32591345
Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia
Review for gene: GNPNAT1 was set to RED
Added comment: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Intellectual disability v3.209 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams Tag for-review tag was added to gene: EEF1A2.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams edited their review of gene: EEF1A2: 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; Changed publications: 32160274
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams commented on gene: EEF1A2
Intellectual disability v3.209 EEF1A2 Eleanor Williams Tag for-review tag was added to gene: EEF1A2.
Intellectual disability v3.209 EEF1A2 Eleanor Williams reviewed gene: EEF1A2: Rating: ; 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: 32160274; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.8 PKD1L1 Zornitza Stark reviewed gene: PKD1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31026592; Phenotypes: Heterotaxy, visceral, 8, autosomal (MIM#617205); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Classified gene: HERC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Gene: herc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.128 HERC2 Arina Puzriakova Tag for-review tag was added to gene: HERC2.
Intellectual disability v3.209 HERC2 Arina Puzriakova Tag for-review tag was added to gene: HERC2.
Intellectual disability v3.209 HERC2 Arina Puzriakova Classified gene: HERC2 as Amber List (moderate evidence)
Intellectual disability v3.209 HERC2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Intellectual disability v3.209 HERC2 Arina Puzriakova Gene: herc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.208 IFT27 Arina Puzriakova Classified gene: IFT27 as Amber List (moderate evidence)
Intellectual disability v3.208 IFT27 Arina Puzriakova Added comment: Comment on list classification: Given the mild ID phenotype, IFT27 is classified Amber on this panel. Patients are more likely to be recognised in view of other features (e.g. Limb disorders panel), for which this gene is Green.
Intellectual disability v3.208 IFT27 Arina Puzriakova Gene: ift27 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.207 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: AMBER; Mode of pathogenicity: None; Publications: 24488770, 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.207 HNMT Arina Puzriakova Classified gene: HNMT as Amber List (moderate evidence)
Intellectual disability v3.207 HNMT Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional unrelated pedigrees are required before inclusion of HNMT on a diagnostic panel (added to watchlist).
Intellectual disability v3.207 HNMT Arina Puzriakova Gene: hnmt has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.206 HNMT Arina Puzriakova Tag watchlist tag was added to gene: HNMT.
Intellectual disability v3.206 HNMT Arina Puzriakova reviewed gene: HNMT: Rating: AMBER; Mode of pathogenicity: None; Publications: 26206890; Phenotypes: Intellectual disability, Mental retardation, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v2.4 ALPK3 Zornitza Stark gene: ALPK3 was added
gene: ALPK3 was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Expert list
Mode of inheritance for gene: ALPK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ALPK3 were set to 26846950; 27106955; 32480058
Phenotypes for gene: ALPK3 were set to Hypertrophic cardiomyopathy
Review for gene: ALPK3 was set to GREEN
gene: ALPK3 was marked as current diagnostic
Added comment: Assessed as Strong by ClinGen (ALPK3-HCM)

4 consanguineous families with ALPK3 biallelic pathogenic variants were identified in 2 papers. 3 families are reported in Alomani (2015) (26846950) and 1 in Phelan (2016) with accompanying functional evidence (27106955). ALPK3 knock out mice develop cardiomyopathy (DCM and HCM) Van Sligtenhorst (2012).

A case series of 19 paeditric cardiomyopathy cases with ALPK3 pathogeic variants concluded: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.
Sources: Expert list
COVID-19 research v1.66 IL6R Arina Puzriakova commented on gene: IL6R
COVID-19 research v1.66 TMEM181 Arina Puzriakova gene: TMEM181 was added
gene: TMEM181 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TMEM181 was set to Unknown
Added comment: Preprint: https://doi.org/10.1101/2020.07.01.20144592
Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection.

TMEM181 SNP (rs117665206, R403C). Authors state that this could be a potentially druggable target for treatment with Cysteamine in COVID-19 patients with this variant. However, whether this genetic variant has any physiological role on SARS-CoV-2 infection is yet to be determined.
Sources: Literature
COVID-19 research v1.65 ALOXE3 Arina Puzriakova gene: ALOXE3 was added
gene: ALOXE3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ALOXE3 was set to Unknown
Added comment: Preprint: https://doi.org/10.1101/2020.07.01.20144592
Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 novel risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection.

Two ALOXE3 SNP (rs147149459, rs151256885) identified. Furthermore, it has been shown that ALOXE3 is upregulated by SARS-CoV in human airway epithelial cultures. However, whether genetic variants have any physiological role on SARS-CoV-2 infection is yet to be determined.
Sources: Literature
COVID-19 research v1.64 ERAP2 Arina Puzriakova changed review comment from: Preprint: https://doi.org/10.1101/2020.07.01.20144592
Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection.

The ERAP2 SNP (rs150892504, R751C) was disruptive to the fold of the protein, in turn decreasing stability. Authors state that this could be a potentially druggable target for treatment with Cysteamine in COVID-19 patients with this variant.
Sources: Literature; to: Preprint: https://doi.org/10.1101/2020.07.01.20144592
Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection.

The ERAP2 SNP (rs150892504, R751C) was disruptive to the fold of the protein, in turn decreasing stability. Authors state that this could be a potentially druggable target for treatment with Cysteamine in COVID-19 patients with this variant. However, whether this genetic variant has any physiological role on SARS-CoV-2 infection is yet to be determined.
Sources: Literature
COVID-19 research v1.64 BRF2 Arina Puzriakova gene: BRF2 was added
gene: BRF2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: BRF2 was set to Unknown
Added comment: Preprint: https://doi.org/10.1101/2020.07.01.20144592
Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 novel risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection.

Structural analysis showed the BRF2 SNP (rs138763430, D9N) at the Zn Ribbon domain alters the electrostatic potential surface, which in turn impacts the fundamental property of the domain to recognise nucleotide binding partners. Thus authors speculate that this variant most likely negatively alters the selectivity of the protein. However, whether this genetic variant has any physiological role on SARS-CoV-2 infection is yet to be determined.
Sources: Literature
COVID-19 research v1.63 ERAP2 Arina Puzriakova gene: ERAP2 was added
gene: ERAP2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ERAP2 was set to Unknown
Added comment: Preprint: https://doi.org/10.1101/2020.07.01.20144592
Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection.

The ERAP2 SNP (rs150892504, R751C) was disruptive to the fold of the protein, in turn decreasing stability. Authors state that this could be a potentially druggable target for treatment with Cysteamine in COVID-19 patients with this variant.
Sources: Literature
COVID-19 research v1.62 TMPRSS2 Arina Puzriakova Tag treatable tag was added to gene: TMPRSS2.
COVID-19 research v1.62 TMPRSS2 Arina Puzriakova commented on gene: TMPRSS2
COVID-19 research v1.62 CD209 Arina Puzriakova commented on gene: CD209
Skeletal dysplasia v2.9 PLEKHM1 Eleanor Williams commented on gene: PLEKHM1: Provisionally associated with ?Osteopetrosis, autosomal recessive 6 #611497 and Osteopetrosis, autosomal dominant 3 #618107 in OMIM.

2 biallelic and 2 monoallelic cases reported. Limited family segregation data and generally targeted sequencing of only a few candidate genes. A mouse model supports the role for this protein in bone re-absorption.

BIALLELIC

PMID: 17404618 - Van Wesenbeeck et al 2007 - report that loss of function variants in the PLEKHM1 gene are responsible for the osteopetrotic phenotype of the incisors absent (ia) rat. They then screened the coding sequence of the PLEKHM1 gene in 43 patients diagnosed with various forms of osteopetrosis and identified a patient with a homozygous G→A transition at position +1 of the donor splice site of intron 3. She was diagnosed with an autosomal-recessive intermediate form of the disease. Her parents, carriers of the mutation, were related to each other and were clinically normal. The oldest brother was heterozygous for the mutation and was clinically and radiologically normal. The youngest brother was homozygous for the mutation but had not yet developed clinical symptoms.

PMID: 28290981 - Moore et al 2017 - report 19 year old white male with history of fractures, as did 2 of his brothers, presenting with clinical osteopetrosis. Genetic testing using the CTGT Osteopetrosis NextGen sequencing panel, consisting of 13 genes associated with osteopetrosis, revealed 2 heterozygous missense mutations in PLEKHM1 (exon 4 and exon 7). No segregation data.

MONOALLELIC

PMID: 27291868 - Bo et al 2016 - report a middle‐aged Chinese man who presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in BMD. A novel de novo heterozygous mutation ( c.3051_3052delCA) in the PLEKHM1 gene was identified, after initial screening of ClCN7 and TNFSF11 genes found no disease causing variants. The patient's unaffected parents and children were also screen and were not found to have the deletion.

PMID: 17997709 - Del Fattore et al 2008 - describe a new heterozygous missense mutation (R714C) in the PLEKHM1 gene in a female Italian patient with generalized osteopenia and localized osteosclerosis, with a diagnosis of osteopetrosis of the skull, However they state that it is NOT a case of osteopetrosis, because in the patient, urine CTX, a marker of in vivo bone resorption, was normal, and in vitro assays of osteoclast formation and resorptive function showed no abnormalities. She was screened for variants only in ClC‐7 and PLEKHM1. No other family members were available for analysis.

MOUSE MODEL
PMID: 27777970 - Fujiwara et al 2016 - Plekhm1-deficient mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Loss of Plekhm1 increased cancellous bone mass due to decreased bone resorption without obvious defects in other tissues and organs.
COVID-19 research v1.62 ACE2 Arina Puzriakova changed review comment from: Preprint: Wooster et al 2020 - https://doi.org/10.1101/2020.06.18.20135152
Analysed association between ACE2 polymorphisms and COVID-19 severity in 62 patients. 10 SNPs were significantly
associated with tissue expression of ACE2. Of these, 6 SNPs were also significantly associated with hospitalisation, after adjusting for sex and age (5 SNPs associated with higher tissue expression and increased need for hospitalisation due to COVID-19; and 1 SNP with lower tissue expression and reduced COVID-19 severity not requiring hospitalisation).; to: Preprint: Wooster et al 2020 - https://doi.org/10.1101/2020.06.18.20135152
Analysed association between ACE2 polymorphisms and COVID-19 severity in 62 patients. 10 SNPs were significantly associated with tissue expression of ACE2. Of these, 6 SNPs were also significantly associated with hospitalisation, after adjusting for sex and age (5 SNPs associated with higher tissue expression and increased need for hospitalisation due to COVID-19; and 1 SNP with lower tissue expression and reduced COVID-19 severity not requiring hospitalisation).
COVID-19 research v1.62 ACE2 Arina Puzriakova commented on gene: ACE2
Intellectual disability v3.206 GNE Arina Puzriakova Classified gene: GNE as Amber List (moderate evidence)
Intellectual disability v3.206 GNE Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of the mild ID phenotype.
Intellectual disability v3.206 GNE Arina Puzriakova Gene: gne has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.205 GNE Arina Puzriakova reviewed gene: GNE: Rating: AMBER; Mode of pathogenicity: None; Publications: 32053088, 29923088, 10356312, 11326336, 11486897, 27142465; Phenotypes: Sialuria, 269921; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Three unrelated cases, but two share the same founder mutation - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.205 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.204 EXOSC8 Arina Puzriakova Tag watchlist tag was added to gene: EXOSC8.
Tag founder-effect tag was added to gene: EXOSC8.
Intellectual disability v3.204 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: AMBER; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia type 1C, 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.204 DSCR3 Arina Puzriakova commented on gene: DSCR3: Added new-gene-name tag, new approved HGNC gene symbol is VPS26C.
Intellectual disability v3.204 DSCR3 Arina Puzriakova Tag new-gene-name tag was added to gene: DSCR3.
Intellectual disability v3.204 DSCR3 Arina Puzriakova Classified gene: DSCR3 as Red List (low evidence)
Intellectual disability v3.204 DSCR3 Arina Puzriakova Added comment: Comment on list classification: Currently not associated with any phenotype in OMIM or G2P. Variants only found in one family - additional cases required to validate pathogenicity.
Intellectual disability v3.204 DSCR3 Arina Puzriakova Gene: dscr3 has been classified as Red List (Low Evidence).
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Classified gene: ATP6AP1 as Amber List (moderate evidence)
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Added comment: Comment on list classification: Unclear whether other ATP6AP1 variants are associated with a neurological phenotype. Amber rating in view of the mild ID phenotype, as a more significant, or consistent pattern, of DD/ID is required (added to watchlist).
Intellectual disability v3.203 ATP6AP1 Arina Puzriakova Gene: atp6ap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.202 ATP6AP1 Arina Puzriakova Tag watchlist tag was added to gene: ATP6AP1.
Intellectual disability v3.202 ATP6AP1 Arina Puzriakova reviewed gene: ATP6AP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27231034; Phenotypes: Immunodeficiency, 300972, Hepatopathy, Intellectual disability, Cutis laxa, Epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.202 PDE10A Arina Puzriakova Classified gene: PDE10A as Amber List (moderate evidence)
Intellectual disability v3.202 PDE10A Arina Puzriakova Added comment: Comment on list classification: Only mild cognitive delay reported in one family. Additional cases with a more significant, or consistent pattern, of DD/ID required to ascertain the contribution of PDE10A variants to an ID phenotype.
Intellectual disability v3.202 PDE10A Arina Puzriakova Gene: pde10a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.201 PDE10A Arina Puzriakova reviewed gene: PDE10A: Rating: AMBER; Mode of pathogenicity: None; Publications: 27058446; Phenotypes: Dyskinesia, limb and orofacial, infantile-onset, 616921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v1.62 LY6E Eleanor Williams commented on gene: LY6E: Preprint - https://doi.org/10.1101/2020.03.05.979260 - Pfaender et al - Mice lacking Ly6e in hematopoietic cells were highly susceptible to murine CoV infection.
Early onset or syndromic epilepsy v2.128 SEC31A Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature
COVID-19 research v1.62 TLR7 Eleanor Williams Publications for gene: TLR7 were set to
COVID-19 research v1.61 TLR7 Eleanor Williams Mode of inheritance for gene: TLR7 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
COVID-19 research v1.60 TLR7 Eleanor Williams reviewed gene: TLR7: Rating: ; Mode of pathogenicity: None; Publications: 32706371; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.201 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

Biallelic pathogenic LARS1 variants cause Infantile liver failure syndrome 1, MIM# 615438.

Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will be most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Early onset or syndromic epilepsy v2.128 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

Biallelic pathogenic LARS1 variants cause Infantile liver failure syndrome 1, MIM# 615438.

Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will be most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Corneal dystrophy v1.3 VSX1 Zornitza Stark gene: VSX1 was added
gene: VSX1 was added to Corneal dystrophies. Sources: Expert list
Mode of inheritance for gene: VSX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: VSX1 were set to Keratoconus 1, MIM# 148300
Review for gene: VSX1 was set to GREEN
gene: VSX1 was marked as current diagnostic
Added comment: Keratoconus is a corneal dystrophy.
Sources: Expert list
Corneal dystrophy v1.3 MIR184 Zornitza Stark reviewed gene: MIR184: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: EDICT syndrome, MIM# 614303; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial Hirschsprung Disease v1.6 SMO Zornitza Stark gene: SMO was added
gene: SMO was added to Familial Hirschsprung Disease. Sources: Expert list
Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMO were set to 32413283
Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis
Review for gene: SMO was set to GREEN
Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Sources: Expert list
Hereditary haemorrhagic telangiectasia v2.4 RASA1 Zornitza Stark reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pulmonary arterial hypertension v2.4 KDR Zornitza Stark gene: KDR was added
gene: KDR was added to Pulmonary arterial hypertension. Sources: Expert list
Mode of inheritance for gene: KDR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDR were set to 31980491
Phenotypes for gene: KDR were set to Pulmonary hypertension
Review for gene: KDR was set to AMBER
Added comment: Two unrelated individuals with PAH and LoF variants reported; segregation evidence in one family.
Sources: Expert list
Pulmonary arterial hypertension v2.4 ABCC8 Zornitza Stark gene: ABCC8 was added
gene: ABCC8 was added to Pulmonary arterial hypertension. Sources: Expert list
Mode of inheritance for gene: ABCC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABCC8 were set to 31406341; 30354297
Phenotypes for gene: ABCC8 were set to Diabetes mellitus; Hypoglycaemia; Pulmonary arterial hypertension
Review for gene: ABCC8 was set to GREEN
gene: ABCC8 was marked as current diagnostic
Added comment: Twelve heterozygous variants identified in PAH cases. Included functional assessment and independent validation of the association with this gene.
Sources: Expert list
Osteogenesis imperfecta v2.6 MBTPS2 Zornitza Stark gene: MBTPS2 was added
gene: MBTPS2 was added to Osteogenesis imperfecta. Sources: Expert list
Mode of inheritance for gene: MBTPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MBTPS2 were set to 27380894
Phenotypes for gene: MBTPS2 were set to Osteogenesis imperfecta, type XIX, MIM# 301014
Review for gene: MBTPS2 was set to AMBER
Added comment: Two unrelated families reported with multiple male affected individuals.
Sources: Expert list
Osteogenesis imperfecta v2.6 UNC45A Zornitza Stark gene: UNC45A was added
gene: UNC45A was added to Osteogenesis imperfecta. Sources: Expert list
Mode of inheritance for gene: UNC45A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45A were set to 29429573
Phenotypes for gene: UNC45A were set to cholestasis; congenital diarrhea; impaired hearing; bone fragility
Review for gene: UNC45A was set to AMBER
Added comment: Bone fragility is present in 3 cases from two families and is not present in another case with biallelic variants. In vitro functional assays suggest loss-of-function mechanism of disease. In vivo zebrafish assays demonstrate defects in gut development and bone fragility doesn't appear to be assessed. Emerging gene-disease association, uncertain if bone fragility is a consistent/prominent feature of the phenotype yet.
Sources: Expert list
Osteogenesis imperfecta v2.6 SGMS2 Zornitza Stark gene: SGMS2 was added
gene: SGMS2 was added to Osteogenesis imperfecta. Sources: Expert list
Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGMS2 were set to 30779713; 32028018
Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550
Review for gene: SGMS2 was set to GREEN
gene: SGMS2 was marked as current diagnostic
Added comment: 12 patients from 6 unrelated families with the same stopgain variant (p.Arg50*), with osteoporosis that resembles osteogenesis imperfecta. In vitro over-expression assays of the variant demonstrate protein that was completely mislocalized in the cytosolic and nuclear compartments.
2 unrelated families were heterozygous for 2 missense (p.Ile62Ser, p.Met64Arg) with bone fragility and severe short stature, and spondylometaphyseal dysplasia. In vitro assays of each variant demonstrated an enhanced rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum.
Sources: Expert list
Osteogenesis imperfecta v2.6 DSPP Zornitza Stark reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dentinogenesis imperfecta 125490; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.201 SMARCA2 Konstantinos Varvagiannis reviewed gene: SMARCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32694869; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.201 MORC2 Konstantinos Varvagiannis gene: MORC2 was added
gene: MORC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688
Penetrance for gene: MORC2 were set to unknown
Mode of pathogenicity for gene: MORC2 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: MORC2 was set to GREEN
Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013).

While several previous studies focused on the phenotype of axonal motor and senory neuropathy in individuals with heterozygous MORC2 pathogenic variants (Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688) some of them presented among others with hypotonia, muscle weakness, intellectual disability, microcephaly or hearing loss [refs provided by Sacoto et al - learning disabilities (in some patients) also listed in OMIM's clinical synopsis].

Sacoto et al present a cohort of 20 individuals having genetic testing for developmental delay or growth failure (with a single one for a diagnosis of sensorimotor neuropathy).

Overlapping features included DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. The authors comment that features suggestive of neuropathy (weakness, hyporeflexia, abnormal EMG/NCS) were frequent but not the predominant complaint. EMG/NCS abnormalities were abnormal in 6 out of 10 subjects investigated in this cohort. Other findings included brain MRI abnormalities (12/18 - in 5/18 Leigh-like lesions), hearing loss (11/19) and pigmentary retinopathy in few (5).

Affected subjects were found to harbor in all cases missense variants in the ATPase module of MORC2 [residues 1 to 494 - NM_001303256.1 - the module consists of an ATPase domain (aa 1-265), a transducer S5-like domain (266-494) and a coiled-coiled domain (CC1 - aa 282-361)].

Variants had occured mostly as de novo events although inheritance from a similarly affected parent was also reported.

Some of them were recurring within this cohort and/or the literature eg. c.79G>A/p.Glu27Lys (x5), c.260C>T/p.Ser87Leu (x2), c.394C>T/p.Arg132Cys (4x), c.1164C>G/p.Ser388Arg (x2), c.1181A>G/p.Tyr394Cys (x3).

MORC2 encodes an ATPase involved in chromatin remodeling, DNA repair and transcriptional regulation. Chromatin remodeling and epigenetic silencing by MORC2 is mediated by the HUSH (Human Silencing Hub) complex. Functional studies (MORC2-knockout HeLa cells harboring a HUSH-sensitive GFP reporter were transduced with wt or mt MORC2 followed by measurement of reporter repression) supported the deleterious effect of most variants known at the time (hyperactivation of HUSH-mediating silencing, in line with previous observations).

Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion.
Sources: Literature
Early onset or syndromic epilepsy v2.128 ASTN1 Arina Puzriakova edited their review of gene: ASTN1: Changed rating: RED
Early onset or syndromic epilepsy v2.128 EIF2A Arina Puzriakova gene: EIF2A was added
gene: EIF2A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EIF2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2A were set to 31130284
Phenotypes for gene: EIF2A were set to Intellectual disability; Seizures; ASD
Review for gene: EIF2A was set to RED
Added comment: Gene is not associated with any phenotype in OMIM or G2P.

PMID: 31130284 - Distinct homozygous variants were identified in two cases presenting an overlapping phenotype of ID and epilepsy (intractable in one patient), as part of a large screening study of a highly consanguineous Saudi population. However, no segregation or follow-up functional studies were conducted to validate the variants, and there is currently no other publication data supporting this candidate gene and the relationship with epilepsy.
Sources: Literature
Intellectual disability v3.201 HIST1H4J Arina Puzriakova changed review comment from: This is a possible gene for intellectual disability with facial dysmorphism in G2P.

Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.; to: Added new-gene-name tag, new approved HGNC gene symbol is H4C11.

This is a possible gene for intellectual disability with facial dysmorphism in G2P.

Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Classified gene: HIST1H4J as Amber List (moderate evidence)
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional cases are required to validate pathogenicity, but added to watchlist.
Intellectual disability v3.201 HIST1H4J Arina Puzriakova Gene: hist1h4j has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.8 TOMM70 Eleanor Williams Classified gene: TOMM70 as Amber List (moderate evidence)
Mitochondrial disorders v2.8 TOMM70 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it was decided to rate this gene as Amber for now, until a clearer phenotype is established and the predominant mode of inheritance is determined.
Mitochondrial disorders v2.8 TOMM70 Eleanor Williams Gene: tomm70 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.7 TOMM70 Eleanor Williams gene: TOMM70 was added
gene: TOMM70 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TOMM70 were set to 31907385; 32356556
Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis; developmental delay; white matter abnormalities
Review for gene: TOMM70 was set to AMBER
Added comment: Not associated with a disease phenotype in OMIM or Gene2Phenotype

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

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

3 cases but different mode of inheritance and phenotypic presentation.
Sources: Literature
Intellectual disability v3.200 HIST1H4J Arina Puzriakova reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: None; Publications: 31804630; Phenotypes: Microcephaly, Intellectual disability, Dysmorphic facial features, Growth delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova edited their review of gene: ADAMTS10: Changed publications: 15368195, 18567016, 19836009, 25469541
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Classified gene: ADAMTS10 as Amber List (moderate evidence)
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Added comment: Comment on list classification: While mild ID is reportedly a phenotypic feature associated with Weill–Marchesani syndrome, this is not evident in the literature cases. Therefore, a more consistent and/or significant pattern of ID is necessary for inclusion of ADAMTS10 on a diagnostic ID panel.
Intellectual disability v3.200 ADAMTS10 Arina Puzriakova Gene: adamts10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.199 ADAMTS10 Arina Puzriakova reviewed gene: ADAMTS10: Rating: AMBER; Mode of pathogenicity: None; Publications: 15368195, 18567016, 19836009; Phenotypes: Weill-Marchesani syndrome, 277600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.199 TOMM70 Eleanor Williams Classified gene: TOMM70 as Amber List (moderate evidence)
Intellectual disability v3.199 TOMM70 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it was decided to rate this gene as Amber for now, until a clearer phenotype is established and the predominant mode of inheritance is determined.
Intellectual disability v3.199 TOMM70 Eleanor Williams Gene: tomm70 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.198 LZTFL1 Arina Puzriakova Classified gene: LZTFL1 as Amber List (moderate evidence)
Intellectual disability v3.198 LZTFL1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.198 LZTFL1 Arina Puzriakova Gene: lztfl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.197 LZTFL1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and probable in G2P. Biallelic variants in the LZTFL1 gene are an established cause of BBS17, with supporting functional data. Cognitive impairment is a feature of the BBS17 associated phenotype in all cases reported to date. Two families have been reported in literature - PMID: 22510444 (2012) - cognitive impairment reported in a 10-year-old BBS17 patient, harbouring a homozygous 5 bp deletion leading to a premature stop codon (c.402-406del, p.Pro136ThrfsX5) in LZTFL1.; to: Associated with phenotype in OMIM and probable in G2P.

Biallelic variants in the LZTFL1 gene are an established cause of BBS17, with supporting functional data. Cognitive impairment is a feature of the BBS17 associated phenotype in all cases reported in literature to date:

PMID: 22510444 (2012) - cognitive impairment reported in a 10-year-old BBS17 patient, harbouring a homozygous 5 bp deletion leading to a premature stop codon (c.402-406del, p.Pro136ThrfsX5) in LZTFL1.

PMID: 23692385 (2014) - cognitive impairment reported in a pair of dizygotic twins with two compound heterozygous LZTFL1 variants ([c.260T>C, p.Leu87Pro];[c.778G>T, p.Glu260*]). One twin was said to have learning difficulties since childhood. She attended a specialised school, and at the age of 36, her educational level was equivalent to the elementary school level. The second twin was also reported to have scholastic difficulties and slowness with an educational level equivalent to primary school.
Intellectual disability v3.197 LYRM7 Arina Puzriakova Classified gene: LYRM7 as Amber List (moderate evidence)
Intellectual disability v3.197 LYRM7 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.197 LYRM7 Arina Puzriakova Gene: lyrm7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.196 LYRM7 Arina Puzriakova Tag for-review tag was added to gene: LYRM7.
Intellectual disability v3.196 LYRM7 Arina Puzriakova changed review comment from: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment. PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one.; to: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment.

PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one. Continued development was delayed to variable degrees in five individuals, and all were said to have impaired intelligence at the time of the most recent assessment (aged 2.5-16 yrs).

PMID: 28694194 (2017) - Three affected family members with homozygosity for a splice site deletion (c.243_244+2delGAGT) in LYRM7. Development was normal for the first few months of life, however all experienced a rapidly progressive clinical course which included profound impairment of psychomotor and mental functions.
Intellectual disability v3.196 LIPT1 Arina Puzriakova Classified gene: LIPT1 as Amber List (moderate evidence)
Intellectual disability v3.196 LIPT1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - cognitive impairment has been reported in more than 3 unrelated surviving patients.
Intellectual disability v3.196 LIPT1 Arina Puzriakova Gene: lipt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.195 LIPT1 Arina Puzriakova Tag for-review tag was added to gene: LIPT1.
Intellectual disability v3.195 LIPT1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM and probable for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase in G2P. LIPT1 deficiency, resulting from bi-allelic variants, is associated with developmental delay, epilepsy, and broad metabolic abnormalities. To date, five unrelated families have been reported with at least one affected child. PMID: 24341803 (2013) - In a boy with LIPT1 deficiency, exome sequencing revealed two heterozygous mutations (c.875C>G and c.535A>G). Psychomotor development was delayed from birth, but sudden further regression occurred at 18 months.; to: Associated with phenotype in OMIM and probable for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase in G2P.

LIPT1 deficiency, resulting from biallelic variants, is associated with developmental delay, epilepsy, and broad metabolic abnormalities. To date, five unrelated families have been reported with at least one affected child.

PMID: 24341803 (2013) - In a boy with LIPT1 deficiency, exome sequencing revealed two compound heterozygous variants (c.875C>G and c.535A>G). Psychomotor development was delayed from birth, but sudden further regression occurred at 18 months. He could not speak but understood simple orders. He was otherwise fully conscious, alert, and he could smile, laugh and follow with eyes. Supporting functional data, including a yeast model.

PMID: 29681092 (2018) – Compound heterozygous variants (c.212C>T and c.539T>C) identified in a male with seizures, severe lactic acidosis, and failure to thrive. Initially he was reportedly developmentally normal; however, due to subsequent neurodevelopmental regression, he had global developmental delays by 21-months-of-age.

PMID 31042466 (2019) – In an 8-year-old female with developmental delay, seizures, and lactic acidosis, WES revealed two compound heterozygous variants (c.875C>G, c.131A>G). Two older sibs died of a similar condition at 7 months and 3 years. Sequencing was not possible in these individuals; however, a healthy sibling did not carry either variant. Functional analysis in patient-derived fibroblasts and mice confirmed LIPT1 deficiency.

In two unrelated families, the phenotype resulted in early infant death, and therefore ID could not be assessed:
PMID: 24256811 (2014) – compound heterozygous missense variants (c.212C>T and c.292C>G) were identified in a female that died on the ninth day of life.
PMID: 27247813 (2016) – compound heterozygous nonsense variants (c.806G>A and c.980T>G) detected in two sibs who both died on the first day of life. A third sibling, who did not harbour these variants, was healthy and thriving at 12 months of life.
Intellectual disability v3.195 KLF7 Arina Puzriakova Classified gene: KLF7 as Amber List (moderate evidence)
Intellectual disability v3.195 KLF7 Arina Puzriakova Gene: klf7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.194 KLF7 Arina Puzriakova Classified gene: KLF7 as Green List (high evidence)
Intellectual disability v3.194 KLF7 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases presenting the relevant phenotype.
Intellectual disability v3.194 KLF7 Arina Puzriakova Gene: klf7 has been classified as Green List (High Evidence).
Intellectual disability v3.193 KLF7 Arina Puzriakova Tag for-review tag was added to gene: KLF7.
Intellectual disability v3.193 KLF7 Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P. Powis et al. (2018) PMID: 29251763 - Heterozygous de novo missense variants were reported in four unrelated individuals. The two females (aged 15 and 16) were both said to have ID; while the two males (aged 2 and 4) had cognitive delay - though ID had not been formally assessed, presumably due to age. Additional features also included motor and speech delay, hypotonia, and neuromuscular symptoms.; to: Not associated with phenotype in OMIM or G2P.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

As discussed by Pohl et al:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

All subjects harbored biallelic pLoF variants.

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

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

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

All subjects harbored biallelic pLoF variants.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

---

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

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

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

The gene has ubiquitous expression, highest in brain.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.
COVID-19 research v0.347 ATF3 Rebecca Foulger commented on gene: ATF3: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3.
PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E).
PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5.
PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.
COVID-19 research v0.347 IRF1 Julie Taylor commented on gene: IRF1: Evidence Summary from Illumina curation team: IRF1 encodes interferon regulatory factor 1, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF1 is constitutively expressed at a low level but significantly elevated upon IFN-I stimulation, elevated IRF1 further amplifies the IFN response through a positive feedback loop (Lukele et al. 2019, Review). IRF-1 attenuates the replication of several viruses, including hepatitis C virus, West Nile virus (WNV), and EMCV, (Schoggins et al 2011) and IRF1 knock out mice are more susceptible to some viruses, such as EMCV and coxsackievirus B3, than wild type mice (Kimura et al. 1994). Using an IRF1 deficient BEAS2B bronchial epithelial cell line with increased susceptibility to VSV, and multiple strains of influenza viruses, Panda et al. 2019, showed that IRF1 is important for the early expression of types I and III IFNs and ISGs.
COVID-19 research v0.347 IDE Alison Coffey commented on gene: IDE: Evidence Summary from Illumina curation team: Insulin-degrading enzyme (IDE), also known as insulysin, is a member of the zinc metalloproteinase family that was initially implicated in insulin degradation. It is highly conserved among different species and has the ability to interact with a variety of functionally unrelated ligands that share little homology in their primary amino acid sequences. Several human viruses use enzymes as receptors. Li et al. (2006) (PMID 17055432) established IDE as a cellular receptor for both cell-free and cell-associated Varicella-zoster virus (VZV), the cause of chickenpox and shingles in humans. VZV is likely spread as cell-free virus to susceptible hosts but transmitted by cell-to-cell spread in the body and in vitro. Li et al. (2006) showed that IDE interacts with the VZV glycoprotein E (gE) (which is essential for virus infection) through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. Li et al. (2010) subsequently reported that a recombinant soluble IDE (rIDE) enhanced VZV infectivity at an early step of infection associated with an increase in virus internalization, and increased cell-to-cell spread. In 2017, Hahn et al. demonstrated that mature HIV-1 p6 protein (stability of which inversely affects the replication capacity of HIV-1) is a substrate for IDE. IDE is both sufficient and required for the degradation of p6, which is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. An IDE specific inhibitor, 6bK, and exogenous insulin, were both shown to interfere with X4-tropic HIV-1 replication in activated PBMCs, most probably by competing with p6 for degradation by IDE. In addition, an IDE-insensitive p6 mutant of HIV-1 exhibits impaired replication capacity but is insensitive to treatment with insulin or 6bK. Conversely, neither virus release and maturation, nor the amounts of particle associated Vpr and p6 itself were altered in IDE knock out cells. The data support a model in which IDE is responsible for the rapid degradation of p6 entering the cell as part of the incoming virion, a process that appears to be crucial to achieve optimal X4-tropic virus replication.
COVID-19 research v0.347 DEFA1 Alison Coffey commented on gene: DEFA1: Evidence Summary from Illumina curation team: DEFA1, or HNP1, is a member of the defensin family of host defense peptides, a group of microbicidal and cytotoxic peptides made by neutrophils. Defensins are known to have a role in innate immunity as a core host-protective component against bacterial, viral and fungal infections (Xu and Wuyaun, 2020). Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses. Defensins also have a potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection and are able to target multiple steps of host-virus interactions to reduce infectivity of both enveloped and non-enveloped viruses. Targets include viral envelopes, glycoproteins, and capsids or host cells. DEFA1 is well-recognized for its direct anti-HIV activity, it also restrains HIV-1 uptake by inhibiting Env-mediated viral fusion and downregulating host cell surface expression of CD4 and coreceptor CXCR4. Post-entry inhibition of enveloped viruses such as HIV-1 and influenza by DEFA1 is mediated through interfering with cell signaling pathways such as PKC that are required for viral replication (Xu and Wuyaun, 2020). An unpublished study by Kit and Kit (2020), demonstrated in silico that the affinity of human alpha-defensins 1, 2, 3 and 5 to SARS-CoV-2 spike protein is higher than that of the SARS-CoV-2 spike protein towards ACE2. The authors suggest that these alpha-defensins may serve as primary factors in protecting lung tissue from COVID-19 viral infection.