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Pituitary hormone deficiency v2.101 TBC1D32 Sarah Leigh reviewed gene: TBC1D32: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.101 TBC1D32 Sarah Leigh Phenotypes for gene: TBC1D32 were changed from to Syndromic Hypopituitarism; orofaciodigital syndrome
Pituitary hormone deficiency v2.100 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32060556; 35875813
Pituitary hormone deficiency v2.99 TBC1D32 Sarah Leigh Mode of inheritance for gene: TBC1D32 was changed from to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.98 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to
Pituitary hormone deficiency v2.97 SOX2 Sarah Leigh Phenotypes for gene: SOX2 were changed from Microphthalmia, syndromic 3 (206900) to Microphthalmia, syndromic 3, OMIM:206900; anophthalmia/microphthalmia-esophageal atresia syndrome, MONDO:0008799
Intellectual disability v3.1726 SCAMP5 Sarah Leigh Tag watchlist was removed from gene: SCAMP5.
Tag Q3_22_rating tag was added to gene: SCAMP5.
Intellectual disability v3.1726 SCAMP5 Sarah Leigh edited their review of gene: SCAMP5: Added comment: PMIDs: 31439720; 33390987 report a total of six indiviuals with de novo heterozygous SCAMP5, p.Gly180Trp variants. All cases had neurodevelopmental disorders including intellectual disability and seizures.; Changed rating: GREEN
Intellectual disability v3.1726 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability v3.1726 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Intellectual disability v3.1726 SCAMP5 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 v3.1726 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1725 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363; 33390987
Intellectual disability v3.1724 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363
Pituitary hormone deficiency v2.96 SIX3 Sarah Leigh Classified gene: SIX3 as Red List (low evidence)
Pituitary hormone deficiency v2.96 SIX3 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.96 SIX3 Sarah Leigh Gene: six3 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.95 SIX3 Sarah Leigh reviewed gene: SIX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.95 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 35951005; 34974160; 32796691
Pituitary hormone deficiency v2.94 SIX3 Sarah Leigh Phenotypes for gene: SIX3 were changed from Holoprosencephaly 2,OMIMM157170 to Holoprosencephaly 2, OMIM:157170; alobar holoprosencephaly, MONDO:0019757
Pituitary hormone deficiency v2.93 SIX3 Sarah Leigh Phenotypes for gene: SIX3 were changed from Holoprosencephaly 2 (157170) to Holoprosencephaly 2,OMIMM157170
Pituitary hormone deficiency v2.92 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 35951005
Pituitary hormone deficiency v2.91 SIX3 Sarah Leigh Publications for gene: SIX3 were set to
Intellectual disability v3.1723 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Structural eye disease v1.148 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Anophthalmia/Microphthalmia to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Intellectual disability v3.1723 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, 611038 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Anophthalmia or microphthalmia v1.50 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Fetal anomalies v1.972 RAX Sarah Leigh Phenotypes for gene: RAX were changed from MICROPHTHALMIA ISOLATED TYPE 3 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Anophthalmia or microphthalmia v1.49 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Anophthalmia or microphthalmia v1.48 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Anophthalmia/Microphthalmia to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Structural eye disease v1.147 RAX Sarah Leigh Publications for gene: RAX were set to 24033328; 14662654; 18783408
Intellectual disability v3.1722 RAX Sarah Leigh Publications for gene: RAX were set to 18039390; 24033328; 30811539; 18783408; 14662654
Intellectual disability v3.1721 RAX Sarah Leigh Publications for gene: RAX were set to 18039390; 24033328
Anophthalmia or microphthalmia v1.47 RAX Sarah Leigh Publications for gene: RAX were set to 30811539; 18783408; 14662654
Fetal anomalies v1.971 RAX Sarah Leigh Publications for gene: RAX were set to
Anophthalmia or microphthalmia v1.46 RAX Sarah Leigh Publications for gene: RAX were set to
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Tag watchlist tag was added to gene: RAX.
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Classified gene: RAX as Amber List (moderate evidence)
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on this panel at the moment..
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Gene: rax has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.89 RAX Sarah Leigh reviewed gene: RAX: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.89 RAX Sarah Leigh Classified gene: RAX as Amber List (moderate evidence)
Pituitary hormone deficiency v2.89 RAX Sarah Leigh Gene: rax has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.88 RAX Sarah Leigh Publications for gene: RAX were set to 30811539
Pituitary hormone deficiency v2.87 RAX Sarah Leigh Phenotypes for gene: RAX were changed from to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Pituitary hormone deficiency v2.86 RAX Sarah Leigh Publications for gene: RAX were set to
Pituitary hormone deficiency v2.85 RAX Sarah Leigh Mode of inheritance for gene: RAX was changed from to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Tag Q3_22_rating tag was added to gene: PCSK1.
Tag Q3_22_NHS_review tag was added to gene: PCSK1.
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Classified gene: PCSK1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Gene: pcsk1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.83 PCSK1 Sarah Leigh reviewed gene: PCSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intestinal failure or congenital diarrhoea v1.50 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from Obesity with impaired prohormone processing, OMIM:600955 to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Severe early-onset obesity v2.51 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from {Obesity, susceptibility to, BMIQ12}, OMIM:612362; Obesity with impaired prohormone processing, 600955; {Obesity, susceptibility to, BMIQ12}, OMIM:612362 to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Pituitary hormone deficiency v2.83 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Intestinal failure or congenital diarrhoea v1.49 PCSK1 Sarah Leigh Publications for gene: PCSK1 were set to
Severe early-onset obesity v2.50 PCSK1 Sarah Leigh Publications for gene: PCSK1 were set to
Pituitary hormone deficiency v2.82 PCSK1 Sarah Leigh Publications for gene: PCSK1 were set to
Pituitary hormone deficiency v2.81 PCSK1 Sarah Leigh Mode of inheritance for gene: PCSK1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 ALPK1 Dmitrijs Rots gene: ALPK1 was added
gene: ALPK1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to 35868845
Phenotypes for gene: ALPK1 were set to ROSAH syndrome
Penetrance for gene: ALPK1 were set to unknown
Mode of pathogenicity for gene: ALPK1 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: ALPK1 was set to GREEN
Added comment: GoF missense variants in ALPK1 cause autoinflammatory condition ROSAH, with most individuals having inflammation, immune therapy available.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 UBA1 Dmitrijs Rots commented on gene: UBA1: NRAS and KRAS SOMATIC variants are included as Amber in this panel
Intellectual disability v3.1720 HK1 Tracy Lester reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm or dissection (GMS) v1.23 ASPH Simon Thomas changed review comment from: Biallelic variants in ASPH are associated with Traboulsi syndrome Jones et al (PMID: 35918038) report seven further individuals from six apparently unrelated families identified through genetics clinics with confirmed molecular diagnoses and features consistent with Traboulsi syndrome. These patients exhibited additional cardiac, musculoskeletal and haematological features thus expanding the phenotypic spectrum of Traboulsi syndrome and demonstrating considerable overlap with Marfan syndrome. Specifically, five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Therefore ASPH should be considered for inclusion in the R125 TAAD/Marfan panel.
Sources: Literature; to: Biallelic variants in ASPH are associated with Traboulsi syndrome Jones et al (PMID: 35918038) report seven further individuals from six apparently unrelated families identified through genetics clinics with confirmed molecular diagnoses and features consistent with Traboulsi syndrome. These patients exhibited additional cardiac, musculoskeletal and haematological features thus expanding the phenotypic spectrum of Traboulsi syndrome and demonstrating considerable overlap with Marfan syndrome. Specifically, five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Therefore ASPH should be considered for inclusion in the R125 TAAD/Marfan panel.
Sources: Literature
Thoracic aortic aneurysm or dissection (GMS) v1.23 ASPH Simon Thomas gene: ASPH was added
gene: ASPH was added to Thoracic aortic aneurysm and dissection. Sources: Literature
Mode of inheritance for gene: ASPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASPH were set to PMID: 35918038
Phenotypes for gene: ASPH were set to ocular features; anterior segment abnormalities; distinctive facial appearance; aortic root dilatation
Penetrance for gene: ASPH were set to unknown
Added comment: Biallelic variants in ASPH are associated with Traboulsi syndrome Jones et al (PMID: 35918038) report seven further individuals from six apparently unrelated families identified through genetics clinics with confirmed molecular diagnoses and features consistent with Traboulsi syndrome. These patients exhibited additional cardiac, musculoskeletal and haematological features thus expanding the phenotypic spectrum of Traboulsi syndrome and demonstrating considerable overlap with Marfan syndrome. Specifically, five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Therefore ASPH should be considered for inclusion in the R125 TAAD/Marfan panel.
Sources: Literature
Early onset or syndromic epilepsy v2.595 CAPRIN1 Konstantinos Varvagiannis edited their review of gene: CAPRIN1: Changed rating: GREEN
Pituitary hormone deficiency v2.80 TCF7L1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TCF7L1.
Tag Q3_22_NHS_review tag was added to gene: TCF7L1.
Pituitary hormone deficiency v2.80 TCF7L1 Sarah Leigh reviewed gene: TCF7L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TGIF1.
Tag Q3_22_NHS_review tag was added to gene: TGIF1.
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh edited their review of gene: TGIF1: Changed rating: GREEN
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh changed review comment from: Associated with Holoprosencephaly 4 (OMIM:142946) and as definitive Gen2Phen gene for Holoprosencephaly. An association between TGIF1 and pituitary hormone deficiency has only been made with three variants in three unrelated cases (PMIDs: 23476075;34440302).; to: Associated with Holoprosencephaly 4 (OMIM:142946) and as definitive Gen2Phen gene for Holoprosencephaly. An association between TGIF1 and pituitary hormone deficiency has only been made with three variants in three unrelated cases (PMIDs: 23476075;34440302).
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Classified gene: TGIF1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review as there are three variants in three unrelated cases with pituitary involvement.
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Gene: tgif1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Deleted their comment
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh edited their review of gene: TGIF1: Added comment: Associated with Holoprosencephaly 4 (OMIM:142946) and as definitive Gen2Phen gene for Holoprosencephaly. An association between TGIF1 and pituitary hormone deficiency has only been made with three variants in three unrelated cases (PMIDs: 23476075;34440302).; Changed rating: AMBER
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Classified gene: TGIF1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on the Pituitary hormone deficiency at the next major review.
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Gene: tgif1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.78 TGIF1 Sarah Leigh Publications for gene: TGIF1 were set to 23476075
Pituitary hormone deficiency v2.77 TGIF1 Sarah Leigh Phenotypes for gene: TGIF1 were changed from Holoprosencephaly 4 (142946) to Holoprosencephaly 4,OMIM:142946; holoprosencephaly 4, MONDO:0007734
Pituitary hormone deficiency v2.76 RNPC3 Sarah Leigh Classified gene: RNPC3 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.76 RNPC3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.76 RNPC3 Sarah Leigh Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.75 RNPC3 Sarah Leigh reviewed gene: RNPC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.75 RNPC3 Sarah Leigh Phenotypes for gene: RNPC3 were changed from Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160 to Pituitary hormone deficiency, combined or isolated 7, OMIM:618160; isolated growth hormone deficiency, type 5, MONDO:0032569
Pituitary hormone deficiency v2.74 RNPC3 Sarah Leigh Tag watchlist was removed from gene: RNPC3.
Tag Q3_22_rating tag was added to gene: RNPC3.
Tag Q3_22_NHS_review tag was added to gene: RNPC3.
Pituitary hormone deficiency v2.74 RNPC3 Sarah Leigh Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814; 33650182
Pituitary hormone deficiency v2.73 WDR11 Sarah Leigh Publications for gene: WDR11 were set to 28453858
Pituitary hormone deficiency v2.72 WDR11 Sarah Leigh reviewed gene: WDR11: Rating: RED; Mode of pathogenicity: None; Publications: 20887964, 34413497, 28453858; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.72 WDR11 Sarah Leigh Publications for gene: WDR11 were set to
Pituitary hormone deficiency v2.71 WDR11 Sarah Leigh Phenotypes for gene: WDR11 were changed from Hypogonadotropic hypogonadism 14 with or without anosmia (614858) to Hypogonadotropic hypogonadism 14 with or without anosmia, OMIM:614858; hypogonadotropic hypogonadism 14 with or without anosmia, MONDO:0013926
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh Tag Q3_21_NHS_review tag was added to gene: ROBO1.
Tag Q3_22_rating tag was added to gene: ROBO1.
Tag Q3_22_MOI tag was added to gene: ROBO1.
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh edited their review of gene: ROBO1: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 28402530 reports three ROBO1 variants in three unrelated cases with pituitary stalk interruption syndrome (MONDO:0019828, which is a non-gene specific phenotype). Segregation is reported for two of these variants: c.2928_2929delG, p.Ala977Glnfs*40 is found in affected dizygotic twins and c.719G>C, p.Cys240Ser is found an affected child and her affected paternal aunt.; Changed rating: GREEN
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh Added comment: Comment on phenotypes: In the context of the Pituitary hormone deficiency panel, the Mondo term: pituitary stalk interruption syndrome (MONDO:0019828) could be applied, however, this Mondo term is a general description and is not specific to a conidition associated with ROBO1 variants.
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh Phenotypes for gene: ROBO1 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.69 ROBO1 Sarah Leigh Publications for gene: ROBO1 were set to
Pituitary hormone deficiency v2.68 ROBO1 Sarah Leigh Mode of inheritance for gene: ROBO1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.67 ROBO1 Sarah Leigh Classified gene: ROBO1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.67 ROBO1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.67 ROBO1 Sarah Leigh Gene: robo1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Tag watchlist tag was added to gene: FAT2.
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Classified gene: FAT2 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the moment, however, if additional FAT2 variants are reported to be associated with pituitary stalk interruption syndrome, this rating may change.
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Gene: fat2 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.65 FAT2 Sarah Leigh edited their review of gene: FAT2: Added comment: Not associated with a pituitary phenotype in OMIM, Gen2Phen or MONDO. PMID: 33108146 reports four FAT2 variants in four unrelated cases with pituitary stalk interruption syndrome (MONDO:0019828, which is a non-gene specific phenotype). However, one of these variants (rs1024234841) is synonymous and in silico tools do not predict an effect on splicing and another variant (rs377026428) is digenic with a DCHS2 variant and so its contribution to disease causation is uncertain.; Changed rating: AMBER
Pituitary hormone deficiency v2.65 FAT2 Sarah Leigh Mode of inheritance for gene: FAT2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.64 FAT2 Sarah Leigh Added comment: Comment on phenotypes: In the context of the Pituitary hormone deficiency panel, the Mondo term: pituitary stalk interruption syndrome (MONDO:0019828) could be applied, however, this Mondo term is a general description and is not specific to a conidition associated with FAT2 variants.
Pituitary hormone deficiency v2.64 FAT2 Sarah Leigh Phenotypes for gene: FAT2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to Spinocerebellar ataxia 45, OMIM:617769; spinocerebellar ataxia 45, MONDO:0033480
Pituitary hormone deficiency v2.63 FAT2 Sarah Leigh Publications for gene: FAT2 were set to 33108146
Pituitary hormone deficiency v2.62 PAX6 Eleanor Williams Classified gene: PAX6 as Red List (low evidence)
Pituitary hormone deficiency v2.62 PAX6 Eleanor Williams Added comment: Comment on list classification: Leaving rating as red, only 1 patient is reported with a variant in PAX and a pituitary hormone deficiency. Another patient is reported with deletion of the enhancer region of PAX6, but the PAX6 coding region was unaffected. Awaiting further cases before considering promoting to amber or green.
Pituitary hormone deficiency v2.62 PAX6 Eleanor Williams Gene: pax6 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.61 PAX6 Eleanor Williams commented on gene: PAX6: PMID: 25342853 - Takagi et al 2015 - studied 88 (syndromic: 30; non-syndromic: 58) Japanese congenital hypopituitarism patients and performed aCGH on the syndromic patients, and analysed PAX6 in all 88 patients. They found 1 heterozygous 310-kb deletion of the PAX6 enhancer region, and 1 non-syndromic patient with a p.N116S variant. Both showed isolated GH deficiency.
Pituitary hormone deficiency v2.61 NKX2-1 Eleanor Williams Classified gene: NKX2-1 as Red List (low evidence)
Pituitary hormone deficiency v2.61 NKX2-1 Eleanor Williams Added comment: Comment on list classification: There is only 1 reported case to date of a patient with haploinsufficiency in NKX2-1 and pituitary hormone deficiency, so rating this gene as red for now.
Pituitary hormone deficiency v2.61 NKX2-1 Eleanor Williams Gene: nkx2-1 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.60 NKX2-1 Eleanor Williams Phenotypes for gene: NKX2-1 were changed from to Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978; brain-lung-thyroid syndrome, MONDO:0012593
Pituitary hormone deficiency v2.59 NKX2-1 Eleanor Williams Publications for gene: NKX2-1 were set to
Pituitary hormone deficiency v2.58 NKX2-1 Eleanor Williams Mode of inheritance for gene: NKX2-1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.57 NKX2-1 Eleanor Williams commented on gene: NKX2-1: Associated with Choreoathetosis, hypothyroidism, and neonatal respiratory distress #610978 (AD) in OMIM.

Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome, Prasad et al 2019 (PMID:31707387) report a case of a patient with profound hypopituitarism in the early neonatal period in addition to undetectable tissue on thyroid ultrasonography, who was subsequently diagnosed with brain-lung-thyroid syndrome. She was found by CGH microarray to have 2 de novo deletions, a 4.9-Mb deletion in 14q13.2-q21.1 and a 404-kb deletion in 3 p12.3-p13. The 14q deletion contains 21 genes including NKX2-1. The deletion of this gene was thought to explain the phenotype.
Pituitary hormone deficiency v2.57 MAGEL2 Eleanor Williams Classified gene: MAGEL2 as Red List (low evidence)
Pituitary hormone deficiency v2.57 MAGEL2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber but with a recommendation for green rating following GMS review. More than 3 patients reported with plausible disease causing variants in MAGEL2 and a pituitary hormone deficiency
Pituitary hormone deficiency v2.57 MAGEL2 Eleanor Williams Gene: magel2 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.56 MAGEL2 Eleanor Williams Phenotypes for gene: MAGEL2 were changed from to Schaaf-Yang syndrome, OMIM:615547; Schaaf-Yang syndrome, MONDO:0014243
Pituitary hormone deficiency v2.55 MAGEL2 Eleanor Williams Publications for gene: MAGEL2 were set to
Pituitary hormone deficiency v2.54 MAGEL2 Eleanor Williams Mode of inheritance for gene: MAGEL2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: MAGEL2.
Tag Q3_22_NHS_review tag was added to gene: MAGEL2.
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: MAGEL2.
Tag Q3_22_rating tag was added to gene: MAGEL2.
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams changed review comment from: Associated with Schaaf-Yang syndrome #615547 (AD) in OMIM.

PMID: 31504653 - Gregory et al 2019 - report 4 patients from 3 unrelated families (2 White European, 1 White Chilean) with the same c.1996dup, p.Q666Pfs*47. variant in MAGEL2, who all presented with variable congenital hypopituitarism (CH) and arthrogryposis. In 2 cases it was found to be a de novo variant. In the other two it would found not to be maternally inherited but paternal DNA was not available.

PMID: 29359444 - Enya et al 2018 - report 3 patients from 2 Japanese families with Schaaf-Yang syndrome with arthrogryposis and endocrinological abnormalities. In both families variants in MAGEL2 were identified (c.1912C>T, p.Gln638*, inherited from the heterozygous father, and the de novo variant c.3131C>A, p.Ser1044*). The patient with the p.Ser1044* was was diagnosed with panhypopituitarism.

PMID: 30323850 - Hidalgo-Santos et al 2018 - report a patient with Schaaf-Yang syndrome and a de novo variant in MAGEL2 (c.3019 C > T, p.Gln1007*). The patient presented with distal contractures, hypotonia, autism spectrum disorder, digestive abnormalities, partial hypopituitarism with central hypothyroidism and growth hormone (GH) deficiency; to: Associated with Schaaf-Yang syndrome #615547 (AD) in OMIM.

PMID: 31504653 - Gregory et al 2019 - report 4 patients from 3 unrelated families (2 White European, 1 White Chilean) with the same c.1996dup, p.Q666Pfs*47. variant in MAGEL2, who all presented with variable congenital hypopituitarism (CH) and arthrogryposis. In 2 cases it was found to be a de novo variant. In the other two it would found not to be maternally inherited but paternal DNA was not available.

PMID: 29359444 - Enya et al 2018 - report 3 patients from 2 Japanese families with Schaaf-Yang syndrome with arthrogryposis and endocrinological abnormalities. In both families variants in MAGEL2 were identified (c.1912C>T, p.Gln638*, inherited from the heterozygous father, and the de novo variant c.3131C>A, p.Ser1044*). The patient with the p.Ser1044* was diagnosed with panhypopituitarism.

PMID: 30323850 - Hidalgo-Santos et al 2018 - report a patient with Schaaf-Yang syndrome and a de novo variant in MAGEL2 (c.3019 C > T, p.Gln1007*). The patient presented with distal contractures, hypotonia, autism spectrum disorder, digestive abnormalities, partial hypopituitarism with central hypothyroidism and growth hormone (GH) deficiency
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams edited their review of gene: MAGEL2: Added comment: Associated with Schaaf-Yang syndrome #615547 (AD) in OMIM.

PMID: 31504653 - Gregory et al 2019 - report 4 patients from 3 unrelated families (2 White European, 1 White Chilean) with the same c.1996dup, p.Q666Pfs*47. variant in MAGEL2, who all presented with variable congenital hypopituitarism (CH) and arthrogryposis. In 2 cases it was found to be a de novo variant. In the other two it would found not to be maternally inherited but paternal DNA was not available.

PMID: 29359444 - Enya et al 2018 - report 3 patients from 2 Japanese families with Schaaf-Yang syndrome with arthrogryposis and endocrinological abnormalities. In both families variants in MAGEL2 were identified (c.1912C>T, p.Gln638*, inherited from the heterozygous father, and the de novo variant c.3131C>A, p.Ser1044*). The patient with the p.Ser1044* was was diagnosed with panhypopituitarism.

PMID: 30323850 - Hidalgo-Santos et al 2018 - report a patient with Schaaf-Yang syndrome and a de novo variant in MAGEL2 (c.3019 C > T, p.Gln1007*). The patient presented with distal contractures, hypotonia, autism spectrum disorder, digestive abnormalities, partial hypopituitarism with central hypothyroidism and growth hormone (GH) deficiency; Changed publications to: 31504653, 29359444, 30323850; Changed phenotypes to: Schaaf-Yang syndrome, OMIM:615547
Pituitary hormone deficiency v2.53 L1CAM Eleanor Williams changed review comment from: Comment on mode of inheritance: Using the default X linked mode of inheritance as only 1 case reported to date in a male, whose mother was a heterozygous carrier. For L1 syndrome female carriers have been noted to show minor features, such as adducted thumbs or mild intellectual deficits.; to: Comment on mode of inheritance: Using the default X linked mode of inheritance as only 1 case reported to date in a male, whose mother was a heterozygous carrier and so there is insufficient evidence to say whether biallelic variants are required for a clinical phenotype in females. For L1 syndrome female carriers have been noted to show minor features, such as adducted thumbs or mild intellectual deficits.
Pituitary hormone deficiency v2.53 L1CAM Eleanor Williams Phenotypes for gene: L1CAM were changed from to CRASH syndrome, OMIM:303350; MASA syndrome, OMIM:303350
Pituitary hormone deficiency v2.52 L1CAM Eleanor Williams Publications for gene: L1CAM were set to
Pituitary hormone deficiency v2.51 L1CAM Eleanor Williams Added comment: Comment on mode of inheritance: Using the default X linked mode of inheritance as only 1 case reported to date in a male, whose mother was a heterozygous carrier. For L1 syndrome female carriers have been noted to show minor features, such as adducted thumbs or mild intellectual deficits.
Pituitary hormone deficiency v2.51 L1CAM Eleanor Williams Mode of inheritance for gene: L1CAM was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.50 L1CAM Eleanor Williams commented on gene: L1CAM: PMID: 31504653 - Gregory et al 2019 - investigated 5 patients from 4 unrelated families who presented with variable congenital hypopituitarism (CH) and arthrogryposis. 1 Afro-Caribbean male patient was found by WES to have a hemizygous L1CAM c.1354G>A, p.G452R variant. This patient also had hydrocephalus and other features consistent with L1 syndrome.
Pituitary hormone deficiency v2.50 KCNQ1 Eleanor Williams commented on gene: KCNQ1: No new evidence reported since the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group at that point agreed that there is insufficient evidence to rate this gene as green. Therefore leaving this gene amber for now.
Pituitary hormone deficiency v2.50 IGSF1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: IGSF1.
Tag Q3_22_NHS_review tag was added to gene: IGSF1.
Pituitary hormone deficiency v2.50 IGSF1 Eleanor Williams Added comment: Comment on mode of inheritance: Heterozygous female carriers may show a phenotype related to the pituitary gland. In PMID: 24108313 (Joustra et al 2013) they report 6 females were biochemically hypothyroid, and 2 were prolactin deficient. (hypothyroid is linked to decreased function of the pituitary gland and prolactin is produced in the pituitary gland). PMID: 30086211 (Roche et al 2018) also report a heterozygous female with central hypothyroidism.

Therefore it is proposed to change the mode of inheritance to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease
Pituitary hormone deficiency v2.50 IGSF1 Eleanor Williams Mode of inheritance for gene: IGSF1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.49 IGSF1 Eleanor Williams edited their review of gene: IGSF1: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.49 IGSF1 Eleanor Williams edited their review of gene: IGSF1: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.49 IGSF1 Eleanor Williams Phenotypes for gene: IGSF1 were changed from Hypothyroidism, central, and testicular enlargement (300888) to Hypothyroidism, central, and testicular enlargement, OMIM:300888
Pituitary hormone deficiency v2.48 IFT172 Eleanor Williams Phenotypes for gene: IFT172 were changed from to retinopathy, metaphyseal dysplasia
Pituitary hormone deficiency v2.47 IFT172 Eleanor Williams Publications for gene: IFT172 were set to
Pituitary hormone deficiency v2.46 IFT172 Eleanor Williams Mode of inheritance for gene: IFT172 was changed from to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.45 IFT172 Eleanor Williams commented on gene: IFT172: PMID: 25664603 - Lucas-Herald et al 2015 - first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood. He responded well to recombinant human growth hormone. He was found by WES to have compound heterozygous variants; a missense mutation, c.5179T>C (p.Cys1727Arg), and a novel splice site mutation in intron 4, c.337–2A>C. The parents were heterozygotes.

A PubMed search did not find any other cases were growth hormone deficiency is reported along with IFT172 variants.
Pituitary hormone deficiency v2.45 GPR161 Eleanor Williams Phenotypes for gene: GPR161 were changed from No OMIM number; pituitary stalk interruption syndrome to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.44 GPR161 Eleanor Williams Mode of inheritance for gene: GPR161 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.43 GPR161 Eleanor Williams commented on gene: GPR161: No phenotype association in OMIM.
As stated previously Karaca et al. (2015) (PMID:25322266) report that a homozygous missense variant IN GPR161 was found in 2 members of a family by WES. Both affected individuals had a clinical diagnosis of Pituitary stalk interruption syndrome (PSIS).
A search of PubMed did not find any further reported cases therefore this gene should remain red at this time.
Pituitary hormone deficiency v2.43 FGFR1 Eleanor Williams changed review comment from: Review on behalf of Professor Mehul Dattani, UCL GOS Institute of Child Health/Great Ormond Street Hospital for Children. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng B, Zhang C, Zhou QY, Chen H, Mohammadi M, Quinton R, Sidis Y, Radovick S,Dattani MT, Pitteloud N.J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.; to: Review on behalf of Professor Mehul Dattani, UCL GOS Institute of Child Health/Great Ormond Street Hospital for Children. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng B, Zhang C, Zhou QY, Chen H, Mohammadi M, Quinton R, Sidis Y, Radovick S,Dattani MT, Pitteloud N.J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.PMID: 22319038
Pituitary hormone deficiency v2.43 FGFR1 Eleanor Williams commented on gene: FGFR1: Review from Professor Dattani confirms that this gene should be green.
Pituitary hormone deficiency v2.43 FGFR1 Eleanor Williams Phenotypes for gene: FGFR1 were changed from Hypogonadotropic hypogonadism 2 with or without anosmia (147950); Hartsfield syndrome (615465); Pfeiffer syndrome (101600); Jackson-Weiss syndrome (123150) to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Jackson-Weiss syndrome, OMIM:123150
Intellectual disability v3.1720 PTPA Konstantinos Varvagiannis gene: PTPA was added
gene: PTPA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability; Parkinsonism
Penetrance for gene: PTPA were set to Complete
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysNDD.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

------

Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Pituitary hormone deficiency v2.42 EIF2S3 Eleanor Williams Phenotypes for gene: EIF2S3 were changed from hypopituitarism; glucose intolerance; MEHMO syndrome, OMIM:300148 to hypopituitarism, MONDO:0005152; glucose intolerance, MONDO:0001076; MEHMO syndrome, OMIM:300148; MEHMO syndrome, MONDO:0010258
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Tag watchlist tag was added to gene: EIF2S3.
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Classified gene: EIF2S3 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Added comment: Comment on list classification: Promoting to Amber. 2 cases reported with hypopituitarism. In another case growth hormone deficiency is noted so adding the watchlist tag.
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Gene: eif2s3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.40 EIF2S3 Eleanor Williams Phenotypes for gene: EIF2S3 were changed from to hypopituitarism; glucose intolerance; MEHMO syndrome, OMIM:300148
Pituitary hormone deficiency v2.39 EIF2S3 Eleanor Williams Publications for gene: EIF2S3 were set to 30878599; 23063529; 27333055,; 28055140
Pituitary hormone deficiency v2.38 EIF2S3 Eleanor Williams Publications for gene: EIF2S3 were set to
Pituitary hormone deficiency v2.37 EIF2S3 Eleanor Williams Added comment: Comment on mode of inheritance: No female cases reported to date.
Pituitary hormone deficiency v2.37 EIF2S3 Eleanor Williams Mode of inheritance for gene: EIF2S3 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.36 EIF2S3 Eleanor Williams Mode of inheritance for gene: EIF2S3 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.35 EIF2S3 Eleanor Williams edited their review of gene: EIF2S3: Added comment: Associated with MEHMO syndrome in OMIM #300148 (XLR)

PMID: 30878599 - Gregory et al 2019 - X-chromosome exome sequencing identified a missense variant in EIF2S3 (p.Pro432Ser) in 3 related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. The authors state this is the first time this combination of phenotypes has been reported in the literature.

Several other studies (PMID: 23063529,PMID: 27333055, PMID: 28055140) report the more severe MEHMO syndrome phenotype with severe learning difficulties, all in males. Heterozygous females are unaffected.
In PMID: 27333055 (Moortgat et al 2016) the growth hormone deficiency is noted in 2 related males, but for 1 it is reported that the pituitary gland and stalk were normal (not mentioned for the other). In PMID: 28055140 (Skopkova et al 2017) panhypopituitarism and partial hypopituitarism are noted as a clinical feature in two unrelated Slovakian patients (both with the same p.Ile465Serfs*4 variant).; Changed phenotypes to: HYPOPITUITARISM, GLUCOSE INTOLERANCE, FEATURES OF MEHMO SYNDROME, MEHMO syndrome, OMIM:300148; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.35 BMP4 Eleanor Williams Classified gene: BMP4 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.35 BMP4 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 3 cases reported, but in one another gene was also deleted, and in the other only 3 genes were sequenced.
Pituitary hormone deficiency v2.35 BMP4 Eleanor Williams Gene: bmp4 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.34 BMP4 Eleanor Williams Phenotypes for gene: BMP4 were changed from Microphthalmia, syndromic 6 (607932) to Microphthalmia, syndromic 6, OMIM:607932
Pituitary hormone deficiency v2.33 BMP4 Eleanor Williams Publications for gene: BMP4 were set to 24289245
Pituitary hormone deficiency v2.32 BMP4 Eleanor Williams commented on gene: BMP4: PMID: 31120642 - Rodríguez-Contreras et al 2019 - report a 6 yo patient with combined pituitary hormone deficiency (CPHD ) who was found to have a de novo pathogenic loss-of-function variant (NM_001202.5:c.794G > A, p.(Trp265*)) in BMP4 following NGS using a custom 310 gene panel. His clinical phenotype included macrocephaly, myopia/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism.

PMID: 24289245 - Breitfeld et al 2014 - sequenced BMP2, 4 and 7 in 19 subjects with combined pituitary hormone deficiency (CPHD). 1 proband was found to have a p.Arg300Pro variant in BMP4 that is predicted to have functional consequences.

PMID: 18252212 - Bakrania et al 2008 - screened 215 individuals with ocular malformation defects for variants in BMP4 and gene deletions by MLPA. They report 1 case with pituitary abormalities along with bilateral anophthalmia, microcephaly, sensorineural deafness, cryptorchidism, partial callosal agenesis, cerebellar abnormalities, and developmental delay . The proband had a deletion of del(14)(q22.2q23.1) which encompasses BMP4 and OTX2. Using in situ hybridization in human embryos, they showed expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits.

Also:
PMID: 35633847 - Calcaterra et al 2022 - report a child with a novel variant p.Glu93* in exon 3 of BMP4. She was found to have an ectopic posterior pituitary but normal hormonal assessment, associated to craniocervical junction dysmorphism and limb anomaly.
Pituitary hormone deficiency v2.32 BRAF Eleanor Williams Classified gene: BRAF as Amber List (moderate evidence)
Pituitary hormone deficiency v2.32 BRAF Eleanor Williams Gene: braf has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Tag Q3_21_NHS_review was removed from gene: BRAF.
Tag Q3_22_NHS_review tag was added to gene: BRAF.
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: BRAF.
Tag Q3_22_rating tag was added to gene: BRAF.
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Classified gene: BRAF as Red List (low evidence)
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with a green recommendation following GMS review. 5 cases reported with functional data implicating pituitary hormone deficiencies.
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Gene: braf has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.30 BRAF Eleanor Williams Phenotypes for gene: BRAF were changed from to Cardiofaciocutaneous syndrome, OMIM:115150; cardiofaciocutaneous syndrome, MONDO:0015280
Pituitary hormone deficiency v2.29 BRAF Eleanor Williams Publications for gene: BRAF were set to
Pituitary hormone deficiency v2.28 BRAF Eleanor Williams Added comment: Comment on mode of pathogenicity: All missense, activating variants
Pituitary hormone deficiency v2.28 BRAF Eleanor Williams Mode of pathogenicity for gene: BRAF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Pituitary hormone deficiency v2.27 BRAF Eleanor Williams Mode of inheritance for gene: BRAF was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.26 BRAF Eleanor Williams edited their review of gene: BRAF: Added comment: PMID: 33795686 - Gualtieri et al 2021 - report 5 unrelated patients with 4 different missense variants in BRAF. WES did not find any other likely causative variants. They all had Cardio-Facio-Cutaneous (CFC) syndrome and were identified to have features of Septo-Optic Dysplasia (SOD). Functional studies using HEK293T cells showed that the BRAF genetic variants are pathogenic and result in activation of the ERK/MAPK pathway. Mice expressing one of the variants found BRAF p.Q257R showed abnormalities in terminal differentiation of hormone-producing cells.; Changed publications to: 33795686; Changed phenotypes to: Cardiofaciocutaneous syndrome, OMIM:115150, cardiofaciocutaneous syndrome, MONDO:0015280
Pituitary hormone deficiency v2.26 ARNT2 Eleanor Williams Classified gene: ARNT2 as Red List (low evidence)
Pituitary hormone deficiency v2.26 ARNT2 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Red. Still only 1 family with variants in this gene and pituitary hormone deficiency reported.
Pituitary hormone deficiency v2.26 ARNT2 Eleanor Williams Gene: arnt2 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.25 ARNT2 Eleanor Williams Phenotypes for gene: ARNT2 were changed from ?Webb-Dattani syndrome (615926) to ?Webb-Dattani syndrome, OMIM:615926
Pituitary hormone deficiency v2.24 ARNT2 Eleanor Williams commented on gene: ARNT2: Provisionally associated with Webb-Dattani syndrome in OMIM (#615926, AR)

As reviewers note PMID: 24022475 - Webb et al 2013 reports a novel homozygous frameshift variant in ARNT2 in a consanguineous family with six affected children. Phenotypic features include microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract.

A search of PubMed did not find any other reported cases.
Skeletal dysplasia v2.217 MYH3 Eleanor Williams Phenotypes for gene: MYH3 were changed from Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 to Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469; contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, MONDO:0008338
Skeletal dysplasia v2.216 MYH3 Eleanor Williams Phenotypes for gene: MYH3 were changed from to Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469
Skeletal dysplasia v2.215 MYH3 Eleanor Williams Classified gene: MYH3 as Amber List (moderate evidence)
Skeletal dysplasia v2.215 MYH3 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a green recommendation following GMS review.
Skeletal dysplasia v2.215 MYH3 Eleanor Williams Gene: myh3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.214 MYH3 Eleanor Williams Tag Q3_22_rating tag was added to gene: MYH3.
Skeletal dysplasia v2.214 MYH3 Eleanor Williams Publications for gene: MYH3 were set to 35169139
Skeletal dysplasia v2.213 MYH3 Eleanor Williams reviewed gene: MYH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25957469, 27381093, 28205584, 29314551, 29805041, 35169139; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Tag watchlist tag was added to gene: DCHS2.
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Classified gene: DCHS2 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review. However, this may change if further DCHS2 variants are found in cases of pituitary stalk interruption syndrome.
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Gene: dchs2 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.23 DCHS2 Sarah Leigh edited their review of gene: DCHS2: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 33108146 reports three DCHS2 variants in three unrelated cases with pituitary stalk interruption syndrome (MONDO:0019828, which is a non-gene specific phenotype). However, one of these variants is digenic with a FAT2 variant and so its contribution to disease causation is uncertain. A Dchs2–/– mouse model has been examined and has defects in hypothalamic-pituitary development, but the phenotype is not consistent with the human condition.; Changed rating: AMBER
Pituitary hormone deficiency v2.23 DCHS2 Sarah Leigh Classified gene: DCHS2 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.23 DCHS2 Sarah Leigh Gene: dchs2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1720 DCHS2 Sarah Leigh Mode of inheritance for gene: DCHS2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.22 DCHS2 Sarah Leigh Mode of inheritance for gene: DCHS2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.21 FAT2 Sarah Leigh Phenotypes for gene: FAT2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.20 FAT2 Sarah Leigh Publications for gene: FAT2 were set to
Pituitary hormone deficiency v2.19 DCHS2 Sarah Leigh Publications for gene: DCHS2 were set to 29165578; 33108146
Intellectual disability v3.1719 DCHS2 Sarah Leigh Added comment: Comment on phenotypes: This Mondo term is a general description and not specific to a conidition associated with DCHS2 variants.
Intellectual disability v3.1719 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.18 DCHS2 Sarah Leigh Added comment: Comment on phenotypes: This Mondo term is a general description and not specific to a conidition associated with DCHS2 variants.
Pituitary hormone deficiency v2.18 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to pituitary stalk interruption syndrome, MONDO:0019828
Intellectual disability v3.1718 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.17 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Intellectual disability v3.1717 DCHS2 Sarah Leigh Publications for gene: DCHS2 were set to 22005931; 26126179; 26876984; 26350204
Pituitary hormone deficiency v2.16 DCHS2 Sarah Leigh Publications for gene: DCHS2 were set to
Intellectual disability v3.1716 CDK9 Sarah Leigh Tag Q3_22_rating was removed from gene: CDK9.
Tag Q3_22_MOI was removed from gene: CDK9.
Tag watchlist tag was added to gene: CDK9.
Intellectual disability v3.1716 CDK9 Sarah Leigh Deleted their comment
Bilateral congenital or childhood onset cataracts v2.111 CDK9 Sarah Leigh Entity copied from Intellectual disability v3.1716
Bilateral congenital or childhood onset cataracts v2.111 CDK9 Sarah Leigh gene: CDK9 was added
gene: CDK9 was added to Cataracts. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: CDK9.
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901
Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures
Penetrance for gene: CDK9 were set to Complete
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Tag watchlist tag was added to gene: NRCAM.
Hereditary spastic paraplegia, childhood onset v2.149 NRCAM Sarah Leigh Tag watchlist tag was added to gene: NRCAM.
Hereditary spastic paraplegia, childhood onset v2.149 NRCAM Sarah Leigh Tag Q3_22_rating was removed from gene: NRCAM.
Tag Q3_22_MOI was removed from gene: NRCAM.
Hereditary spastic paraplegia, childhood onset v2.149 NRCAM Sarah Leigh Deleted their comment
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Deleted their comment
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Tag Q3_22_rating was removed from gene: NRCAM.
Tag Q3_22_MOI was removed from gene: NRCAM.
Hereditary spastic paraplegia, childhood onset v2.149 NRCAM Sarah Leigh Entity copied from Intellectual disability v3.1716
Hereditary spastic paraplegia, childhood onset v2.149 NRCAM Sarah Leigh gene: NRCAM was added
gene: NRCAM was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: NRCAM.
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Penetrance for gene: NRCAM were set to Complete
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Entity copied from Intellectual disability v3.1716
Skeletal dysplasia v2.213 NRCAM Sarah Leigh gene: NRCAM was added
gene: NRCAM was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: NRCAM.
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Penetrance for gene: NRCAM were set to Complete
Intellectual disability v3.1716 ANK3 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ANK3.
Tag Q3_22_rating tag was added to gene: ANK3.
Tag Q3_22_NHS_review tag was added to gene: ANK3.
Intellectual disability v3.1716 ANK3 Sarah Leigh Added comment: Comment on mode of inheritance: Due to the reports of heterozygous variants in PMIDs: 23390136; 28687526; 34218362, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1716 ANK3 Sarah Leigh Mode of inheritance for gene: ANK3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1715 ANK3 Sarah Leigh Classified gene: ANK3 as Amber List (moderate evidence)
Intellectual disability v3.1715 ANK3 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 v3.1715 ANK3 Sarah Leigh Gene: ank3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1714 ANK3 Sarah Leigh edited their review of gene: ANK3: Added comment: Associated with Intellectual developmental disorder, autosomal recessive 37 (OMIM:615493) in OMIM, but not associated with a phenotype in Gen2Phen. At least six ANK3 variants have now been associated with an autosomal dominant neurodevelopmental condition (PMIDs: 23390136; 28687526; 34218362). These terminating variants affect the transcripts for all of the ANK3 isoforms and are de novo (where trio evidence is available).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1714 ANK3 Sarah Leigh Publications for gene: ANK3 were set to 23390136; 34218362
Intellectual disability v3.1713 ANK3 Sarah Leigh Phenotypes for gene: ANK3 were changed from ?Mental retardation, autosomal recessive, 37 615493 to Intellectual developmental disorder, autosomal recessive 37, OMIM:615493; intellectual disability-hypotonia-spasticity-sleep disorder syndrome, MONDO:0014210
Intellectual disability v3.1712 ANK3 Sarah Leigh Publications for gene: ANK3 were set to 23390136
Pituitary hormone deficiency v2.15 DCHS2 Eleanor Williams reviewed gene: DCHS2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: PSIS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 ROBO1 Eleanor Williams reviewed gene: ROBO1: Rating: ; Mode of pathogenicity: ; Publications: 28402530; Phenotypes: PSIS, VARIABLE EYE ABNORMALITIES; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 WDR11 Eleanor Williams reviewed gene: WDR11: Rating: ; Mode of pathogenicity: ; Publications: 28453858; Phenotypes: PITUITARY STALK INTERRUPTION SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 TGIF1 Eleanor Williams reviewed gene: TGIF1: Rating: ; Mode of pathogenicity: ; Publications: 34440302; Phenotypes: HYPOPITUITARISM, HOLOPROSENCEPHALY; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 TCF7L1 Eleanor Williams reviewed gene: TCF7L1: Rating: ; Mode of pathogenicity: ; Publications: 26764381; Phenotypes: SEPTO-OPTIC DYSPLASIA; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 TBC1D32 Eleanor Williams reviewed gene: TBC1D32: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: HYPOPITUITARISM, OROFACIODIGITAL SYNDROME FEATURES, POLYDACTYLY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 SOX2 Eleanor Williams reviewed gene: SOX2: Rating: ; Mode of pathogenicity: ; Publications: 16932809; Phenotypes: SEVERE EYE DEFECTS, DIPLEGIA, HYPOGONADOTROPHIC HYPOGONADISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 SIX3 Eleanor Williams reviewed gene: SIX3: Rating: ; Mode of pathogenicity: ; Publications: 35951005; Phenotypes: HYPOPITUITARISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 RNPC3 Eleanor Williams reviewed gene: RNPC3: Rating: ; Mode of pathogenicity: ; Publications: 34906446; Phenotypes: GHT, TSH AND PROLACTIN DEFICIENCY, PRIMARY OVARIAN FAILURE, NEUROPATHY, INTELLECTUAL DISABILITY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 RAX Eleanor Williams reviewed gene: RAX: Rating: ; Mode of pathogenicity: ; Publications: 30811539; Phenotypes: ANOPHTHALMIA, CLAEFT PALATE, DIABETES INSIPIDUS, HYPOPITUITARISM; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 PCSK1 Eleanor Williams reviewed gene: PCSK1: Rating: ; Mode of pathogenicity: ; Publications: 30383237; Phenotypes: CONGENITAL DIARRHOEA, HYPOPITUITARISM, OBESITY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 PAX6 Eleanor Williams reviewed gene: PAX6: Rating: ; Mode of pathogenicity: ; Publications: 25342853; Phenotypes: EYE ABNORMALITIES, GH DEFICIENCY; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 NKX2-1 Eleanor Williams reviewed gene: NKX2-1: Rating: ; Mode of pathogenicity: ; Publications: 31707387; Phenotypes: BRAIN-THYROID-LUNG SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 MAGEL2 Eleanor Williams reviewed gene: MAGEL2: Rating: ; Mode of pathogenicity: ; Publications: 31504653; Phenotypes: SCHAAF-YANG SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Pituitary hormone deficiency v2.15 L1CAM Eleanor Williams reviewed gene: L1CAM: Rating: ; Mode of pathogenicity: ; Publications: 31504653; Phenotypes: HYDROCEPHALUS, ARTHROGRYPOSIS; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.15 KCNQ1 Eleanor Williams reviewed gene: KCNQ1: Rating: ; Mode of pathogenicity: ; Publications: 29097701; Phenotypes: Maternally inherited gingival fibromatosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 IGSF1 Eleanor Williams reviewed gene: IGSF1: Rating: ; Mode of pathogenicity: ; Publications: 23143598; Phenotypes: MACRO-ORCHIDISM, TSH, GH AND PROLACTIN DEFICIENCIES,; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.15 IFT172 Eleanor Williams reviewed gene: IFT172: Rating: ; Mode of pathogenicity: ; Publications: 25664603; Phenotypes: RETINOPATHY, METAPHYSEAL DYSPLASIA; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 GPR161 Eleanor Williams reviewed gene: GPR161: Rating: ; Mode of pathogenicity: ; Publications: 25322266; Phenotypes: PITUITARY STALK INTERRUPTION SYNDROME; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 FGFR1 Eleanor Williams reviewed gene: FGFR1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: CLEFT LIP/PALATE, OPTIC NERVE HYPOPLASIA; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 FAT2 Eleanor Williams reviewed gene: FAT2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: PITUITARY STALK INTERRUPTION SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 EIF2S3 Eleanor Williams reviewed gene: EIF2S3: Rating: ; Mode of pathogenicity: ; Publications: 30878599; Phenotypes: HYPOPITUITARISM, GLUCOSE INTOLERANCE, FEATURES OF MEHMO SYNDROME; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.15 BMP4 Eleanor Williams reviewed gene: BMP4: Rating: ; Mode of pathogenicity: ; Publications: 31120642; Phenotypes: LEARNING DIFFICULTIES; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 BRAF Eleanor Williams reviewed gene: BRAF: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: CARDIOFACIOCUTANEOUS SYNDROME + HYPOPITUITARISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 ARNT2 Eleanor Williams reviewed gene: ARNT2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: HYPOPITUITARISM, LEARNING DIFFICULTIES, MICROCEPHALY, DIABETES INSIPIDUS; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.14 DCHS2 Eleanor Williams gene: DCHS2 was added
gene: DCHS2 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: DCHS2 was set to
Pituitary hormone deficiency v2.14 ROBO1 Eleanor Williams gene: ROBO1 was added
gene: ROBO1 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: ROBO1 was set to
Pituitary hormone deficiency v2.14 TBC1D32 Eleanor Williams gene: TBC1D32 was added
gene: TBC1D32 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: TBC1D32 was set to
Pituitary hormone deficiency v2.14 RAX Eleanor Williams gene: RAX was added
gene: RAX was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: RAX was set to
Pituitary hormone deficiency v2.14 PCSK1 Eleanor Williams gene: PCSK1 was added
gene: PCSK1 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: PCSK1 was set to
Pituitary hormone deficiency v2.14 NKX2-1 Eleanor Williams gene: NKX2-1 was added
gene: NKX2-1 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: NKX2-1 was set to
Pituitary hormone deficiency v2.14 MAGEL2 Eleanor Williams gene: MAGEL2 was added
gene: MAGEL2 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: MAGEL2 was set to
Pituitary hormone deficiency v2.14 L1CAM Eleanor Williams gene: L1CAM was added
gene: L1CAM was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: L1CAM was set to
Pituitary hormone deficiency v2.14 IFT172 Eleanor Williams gene: IFT172 was added
gene: IFT172 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: IFT172 was set to
Pituitary hormone deficiency v2.14 FAT2 Eleanor Williams gene: FAT2 was added
gene: FAT2 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: FAT2 was set to
Pituitary hormone deficiency v2.14 EIF2S3 Eleanor Williams gene: EIF2S3 was added
gene: EIF2S3 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: EIF2S3 was set to
Pituitary hormone deficiency v2.14 BRAF Eleanor Williams gene: BRAF was added
gene: BRAF was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: BRAF was set to
Neonatal diabetes v2.40 ZNF808 Eleanor Williams reviewed gene: ZNF808: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Neonatal diabetes, pancreatic agenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.40 ONECUT1 Eleanor Williams reviewed gene: ONECUT1: Rating: ; Mode of pathogenicity: ; Publications: 34663987; Phenotypes: Neonatal diabetes, pancreatic agenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.40 FICD Eleanor Williams reviewed gene: FICD: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Neonatal diabetes, severe neurodevelopmental delay and skeletal abnormalities.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.40 EIF2B1 Eleanor Williams reviewed gene: EIF2B1: Rating: ; Mode of pathogenicity: ; Publications: 31882561; Phenotypes: Permanent neonatal/early onset diabetes and transient liver dysfunction.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v2.40 CNOT1 Eleanor Williams reviewed gene: CNOT1: Rating: ; Mode of pathogenicity: ; Publications: 31006513, 35481434, 31006510; Phenotypes: Neonatal diabetes, pancreatic agenesis and holoprosencephaly.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v2.39 ZNF808 Eleanor Williams gene: ZNF808 was added
gene: ZNF808 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: ZNF808 was set to
Neonatal diabetes v2.39 ONECUT1 Eleanor Williams gene: ONECUT1 was added
gene: ONECUT1 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: ONECUT1 was set to
Neonatal diabetes v2.39 FICD Eleanor Williams gene: FICD was added
gene: FICD was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: FICD was set to
Neonatal diabetes v2.39 EIF2B1 Eleanor Williams gene: EIF2B1 was added
gene: EIF2B1 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: EIF2B1 was set to
Neonatal diabetes v2.39 CNOT1 Eleanor Williams gene: CNOT1 was added
gene: CNOT1 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: CNOT1 was set to
Congenital hyperinsulinism v2.12 NSD1 Eleanor Williams reviewed gene: NSD1: Rating: ; Mode of pathogenicity: ; Publications: :30719864; Phenotypes: Hyperinsulinaemic hypoglycaemia, distinctive facial features, overgrowth in childhood and developmental delay.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.12 MAGEL2 Eleanor Williams reviewed gene: MAGEL2: Rating: ; Mode of pathogenicity: ; Publications: 25473036, 29599419, 31397880; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Congenital hyperinsulinism v2.12 HK1 Eleanor Williams reviewed gene: HK1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital hyperinsulinism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.12 CACNA1D Eleanor Williams reviewed gene: CACNA1D: Rating: ; Mode of pathogenicity: ; Publications: 28318089, 32336187; Phenotypes: congenital hyperinsulinism, hypotonia and heart defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.12 CACNA1C Eleanor Williams reviewed gene: CACNA1C: Rating: ; Mode of pathogenicity: ; Publications: 35897673; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.11 MAGEL2 Eleanor Williams gene: MAGEL2 was added
gene: MAGEL2 was added to Congenital hyperinsulinism. Sources: Expert review
Mode of inheritance for gene: MAGEL2 was set to
Congenital hyperinsulinism v2.11 HK1 Eleanor Williams gene: HK1 was added
gene: HK1 was added to Congenital hyperinsulinism. Sources: Expert review
Mode of inheritance for gene: HK1 was set to
Congenital hyperinsulinism v2.11 CACNA1C Eleanor Williams gene: CACNA1C was added
gene: CACNA1C was added to Congenital hyperinsulinism. Sources: Expert review
Mode of inheritance for gene: CACNA1C was set to
Intellectual disability v3.1711 DOCK8 Sarah Leigh Tag Q3_22_rating tag was added to gene: DOCK8.
Tag Q3_22_MOI tag was added to gene: DOCK8.
Tag Q3_22_NHS_review tag was added to gene: DOCK8.
Tag Q3_22_expert_review tag was added to gene: DOCK8.
Intellectual disability v3.1711 DOCK8 Sarah Leigh Added comment: Comment on phenotypes: Biallelic DOCK8 variants are associated with Hyper-IgE recurrent infection syndrome, autosomal recessive, OMIM:243700;combined immunodeficiency due to DOCK8 deficiency, MONDO:0009478
Intellectual disability v3.1711 DOCK8 Sarah Leigh Phenotypes for gene: DOCK8 were changed from Mental retardation, autosomal dominant 2, 614113Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; HYPERIMMUNOGLOBULIN E RECURRENT INFECTION SYNDROME AUTOSOMAL RECESSIVE (AR-HIES) to Intellectual developmental disorder, autosomal dominant 2, OMIM:614113
Intellectual disability v3.1710 DOCK8 Sarah Leigh reviewed gene: DOCK8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 2, OMIM:614113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1710 DOCK8 Sarah Leigh Publications for gene: DOCK8 were set to
Early onset or syndromic epilepsy v2.595 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Developmental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Intellectual disability v3.1709 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Developemental and epileptic encephalopathy 42, OMIM:617106 to Developemental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917
Intellectual disability v3.1708 CACNA1A Sarah Leigh Publications for gene: CACNA1A were set to 24896178; 27476654
Intellectual disability v3.1707 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh edited their review of gene: CACNA1A: Added comment: PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 36063114, 34267336, 33445191, 27250579; Changed phenotypes to: Developmental and epileptic encephalopathy 42, OMIM:617106; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1707 CACNA1A Sarah Leigh edited their review of gene: CACNA1A: Added comment: PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 36063114, 34267336, 33445191, 27250579; Changed phenotypes to: Developmental and epileptic encephalopathy 42, OMIM:617106; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh Publications for gene: CACNA1A were set to 29056246; 27476654; 11564488; 20071244; 15452324; 8898206
Neurodegenerative disorders, adult onset v2.287 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Neurodegenerative disorders, adult onset v2.287 STUB1 Sarah Leigh Tag Q3_22_MOI was removed from gene: STUB1.
Intellectual disability v3.1707 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Intellectual disability v3.1707 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.261 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Dystonia, chorea or related movement disorder, childhood onset v1.261 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.287 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Cerebellar hypoplasia v1.67 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Cerebellar hypoplasia v1.67 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.308 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Hereditary ataxia v1.308 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.305 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Ataxia and cerebellar anomalies - childhood onset v2.305 STUB1 Sarah Leigh reviewed gene: STUB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.287 STUB1 Sarah Leigh reviewed gene: STUB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.162 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Hereditary ataxia, adult onset v2.162 STUB1 Sarah Leigh reviewed gene: STUB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.307 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Ataxia and cerebellar anomalies - childhood onset v2.305 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Brain channelopathy v1.80 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.80 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to
Parkinson Disease and Complex Parkinsonism v1.110 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Parkinson Disease and Complex Parkinsonism v1.109 TBP Sarah Leigh Publications for gene: TBP were set to
Neurodegenerative disorders, adult onset v2.287 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Hereditary ataxia, adult onset v2.162 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Ataxia and cerebellar anomalies - childhood onset v2.304 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16; Spinocerebellar ataxia, autosomal recessive 16 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Intellectual disability v3.1706 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16, 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Hereditary ataxia v1.306 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Cerebellar hypoplasia v1.66 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Dystonia, chorea or related movement disorder, childhood onset v1.260 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16, 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Neurodegenerative disorders, adult onset v2.286 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Hereditary ataxia, adult onset v2.161 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Autosomal recessive spinocerebellar ataxia type 16, 615768; Spinocerebellar ataxia, autosomal recessive 16 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Intellectual disability v3.1705 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 24312598
Dystonia, chorea or related movement disorder, childhood onset v1.259 STUB1 Sarah Leigh Publications for gene: STUB1 were set to
Cerebellar hypoplasia v1.65 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 24312598
Hereditary ataxia v1.305 STUB1 Sarah Leigh Publications for gene: STUB1 were set to
Ataxia and cerebellar anomalies - childhood onset v2.303 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 24312598
Hereditary ataxia, adult onset v2.160 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 32713943; 33564152; 35493319; 34906452
Neurodegenerative disorders, adult onset v2.285 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 25592071; 30381368
Hereditary ataxia, adult onset v2.159 STUB1 Sarah Leigh Publications for gene: STUB1 were set to
Early onset or syndromic epilepsy v2.593 DNAJC6 Dmitrijs Rots changed review comment from: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 cases had movement disorder and homozygous variant (nonsense, splice, frameshift and missense) and 3/6 cases had seizures reported.; to: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 studies had movement disorder and homozygous variant (nonsense, splice, frameshift and missense) and 3/6 studies had seizures reported.
Dystonia, chorea or related movement disorder, childhood onset v1.258 DNAJC6 Dmitrijs Rots gene: DNAJC6 was added
gene: DNAJC6 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: DNAJC6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC6 were set to 34175496
Review for gene: DNAJC6 was set to AMBER
Added comment: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 studies had childhood-onset movement disorder (mostly parkinsonism) and homozygous variant (nonsense, splice, frameshift and missense).
Sources: Literature
Early onset or syndromic epilepsy v2.593 DNAJC6 Dmitrijs Rots reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 34175496; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.212 MYH3 Dmitrijs Rots gene: MYH3 was added
gene: MYH3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MYH3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYH3 were set to 35169139
Review for gene: MYH3 was set to GREEN
Added comment: 17 individuals with variable vertebral and spine anomalies, as well as short stature reported in 35169139. Pathogenic variants in MYH3 cause not only Arthrogryposis.
Sources: Literature
Structural eye disease v1.146 NR2F1 Eleanor Williams Classified gene: NR2F1 as Red List (low evidence)
Structural eye disease v1.146 NR2F1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red as 1 case reported.
Structural eye disease v1.146 NR2F1 Eleanor Williams Gene: nr2f1 has been classified as Red List (Low Evidence).
Structural eye disease v1.145 NR2F1 Eleanor Williams Mode of pathogenicity for gene: NR2F1 was changed from Other to None
Structural eye disease v1.144 NR2F1 Eleanor Williams changed review comment from: As Samantha Malka reports PMID:34787370 (Gazdagh et al 2022) report a severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) in a patient with a de novo missense variant in the start codon of the NR2F1 gene. The patient showed a typical BBSOAS phenotype with developmental delay, seizures, optic atrophy however this patient also had colobomas and septo-optic dysplasia.; to: As Samantha Malka comments PMID:34787370 (Gazdagh et al 2022) report a severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) in a patient with a de novo missense variant in the start codon of the NR2F1 gene. The patient showed a typical BBSOAS phenotype with developmental delay, seizures, optic atrophy however this patient also had colobomas and septo-optic dysplasia.
Structural eye disease v1.144 NR2F1 Eleanor Williams commented on gene: NR2F1
Structural eye disease v1.144 NR2F1 Eleanor Williams Publications for gene: NR2F1 were set to PMID: 34787370
Structural eye disease v1.143 NR2F1 Eleanor Williams Phenotypes for gene: NR2F1 were changed from Bosch-Boonstra-Schaaf optic atrophy syndrome to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722; Bosch-Boonstra-Schaaf optic atrophy syndrome, MONDO:0014320
Structural eye disease v1.142 KIF7 Eleanor Williams Classified gene: KIF7 as Red List (low evidence)
Structural eye disease v1.142 KIF7 Eleanor Williams Added comment: Comment on list classification: Leaving rating as red. Although a second case with a variant in KIF7 is reported in Niceta et al (2020) the patient also has a homozygous variant in KIAA0556.
Structural eye disease v1.142 KIF7 Eleanor Williams Gene: kif7 has been classified as Red List (Low Evidence).
Structural eye disease v1.141 KIF7 Eleanor Williams Publications for gene: KIF7 were set to 21633164
Structural eye disease v1.140 KIAA0556 Eleanor Williams Classified gene: KIAA0556 as Red List (low evidence)
Structural eye disease v1.140 KIAA0556 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red as one case reported with structural eye phenotype but the individual also had a biallelic variant in KIF7.
Structural eye disease v1.140 KIAA0556 Eleanor Williams Gene: kiaa0556 has been classified as Red List (Low Evidence).
Structural eye disease v1.139 KIAA0556 Eleanor Williams Phenotypes for gene: KIAA0556 were changed from Joubert syndrome 26 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Structural eye disease v1.138 KIAA0556 Eleanor Williams Publications for gene: KIAA0556 were set to PMID: 32164589
Structural eye disease v1.137 EP300 Eleanor Williams Classified gene: EP300 as Red List (low evidence)
Structural eye disease v1.137 EP300 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red as 1 case with a structural eye phenotype reported
Structural eye disease v1.137 EP300 Eleanor Williams Gene: ep300 has been classified as Red List (Low Evidence).
Structural eye disease v1.136 EP300 Eleanor Williams Mode of inheritance for gene: EP300 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.135 EP300 Eleanor Williams Phenotypes for gene: EP300 were changed from Rubinstein-Taybi syndrome 2 to Rubinstein-Taybi syndrome 2, OMIM:613684; Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, MONDO:0013364
Structural eye disease v1.134 EP300 Eleanor Williams Publications for gene: EP300 were set to PMID: 26279656
Structural eye disease v1.133 EP300 Eleanor Williams Mode of pathogenicity for gene: EP300 was changed from Other to None
Structural eye disease v1.132 EP300 Eleanor Williams commented on gene: EP300
Stickler syndrome v2.35 BMP4 Eleanor Williams changed review comment from: Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert.; to: Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert. Therefore it is recommended for a green rating following GMS review.
Stickler syndrome v2.35 BMP4 Eleanor Williams Classified gene: BMP4 as Amber List (moderate evidence)
Stickler syndrome v2.35 BMP4 Eleanor Williams Added comment: Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert.
Stickler syndrome v2.35 BMP4 Eleanor Williams Gene: bmp4 has been classified as Amber List (Moderate Evidence).
Stickler syndrome v2.34 BMP4 Eleanor Williams Publications for gene: BMP4 were set to 30568244
Stickler syndrome v2.33 BMP4 Eleanor Williams Mode of inheritance for gene: BMP4 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Stickler syndrome v2.32 BMP4 Eleanor Williams Tag Q3_22_rating tag was added to gene: BMP4.
Tag Q3_22_NHS_review tag was added to gene: BMP4.
Stickler syndrome v2.32 BMP4 Eleanor Williams commented on gene: BMP4
Stickler syndrome v2.32 VCAN Eleanor Williams Mode of inheritance for gene: VCAN was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Stickler syndrome v2.31 VCAN Eleanor Williams Classified gene: VCAN as Amber List (moderate evidence)
Stickler syndrome v2.31 VCAN Eleanor Williams Added comment: Comment on list classification: Promoted from grey to amber, with a recommendation for green rating following GMS expert review to decide whether this gene is appropriate for the panel.
Stickler syndrome v2.31 VCAN Eleanor Williams Gene: vcan has been classified as Amber List (Moderate Evidence).
Stickler syndrome v2.30 VCAN Eleanor Williams Tag Q3_22_rating tag was added to gene: VCAN.
Tag Q3_22_NHS_review tag was added to gene: VCAN.
Tag Q3_22_expert_review tag was added to gene: VCAN.
Stickler syndrome v2.30 VCAN Eleanor Williams Phenotypes for gene: VCAN were changed from Ocular-only Stickler syndrome; Wagner syndrome to Ocular-only Stickler syndrome; Wagner syndrome 1, OMIM:143200
Stickler syndrome v2.29 VCAN Eleanor Williams Publications for gene: VCAN were set to Snead M, Richards A. A frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration. Am J Ophthalmol. 2002 Sep; 134(3):473; author reply 473-4. doi: 10.1016/s0002-9394(02)01635-5. PMID: 12208278.
Stickler syndrome v2.28 VCAN Eleanor Williams Added comment: Comment on mode of pathogenicity: Disease associated variants all affect splicing.
Stickler syndrome v2.28 VCAN Eleanor Williams Mode of pathogenicity for gene: VCAN was changed from None to Other
Stickler syndrome v2.27 VCAN Eleanor Williams commented on gene: VCAN
Early onset or syndromic epilepsy v2.593 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 23252400; 31584066
Congenital disorders of glycosylation v2.94 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 23252400
Likely inborn error of metabolism v2.321 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Undiagnosed metabolic disorders v1.564 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
DDG2P v2.81 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 17120046
Fetal anomalies v1.970 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Intellectual disability v3.1704 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Congenital disorders of glycosylation v2.93 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Epileptic encephalopathy, early infantile, 15 615006; ST3GAL3-CDG (Disorders of protein N-glycosylation) to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Likely inborn error of metabolism v2.320 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Intellectual disability; Epileptic encephalopathy, early infantile, 15 615006; ST3GAL3-CDG (Disorders of protein N-glycosylation) to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Undiagnosed metabolic disorders v1.563 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from ST3GAL3-CDG (Disorders of protein N-glycosylation); Intellectual disability to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Fetal anomalies v1.969 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
DDG2P v2.80 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 611090 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Intellectual disability v3.1703 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Mental retardation, autosomal recessive 12, 611090Epileptic encephalopathy, early infantile, 15, 615006; MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Early onset or syndromic epilepsy v2.592 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Epileptic encephalopathy, early infantile, 15 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Early onset or syndromic epilepsy v2.591 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh Tag watchlist tag was added to gene: HEATR3.
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh edited their review of gene: HEATR3: Added comment: After consultation with Helen Brittain (Clinical Fellow, Genomics England), is was concluded that there is not enough evidence for skeletal dysplasia in the cases reported in PMID: 35213692 for HEATR3 to be rated green on this panel, as the height of the affected individuals ranged from <–4 SD to normal.; Changed rating: AMBER
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh Tag Q3_22_rating was removed from gene: HEATR3.
Tag Q3_22_MOI was removed from gene: HEATR3.
Limb disorders v2.81 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. HEATR3 has been rated as Green as the affected members of 3/4 families identified had brachydactyly and other features of hands and/or feet.
Limb disorders v2.81 HEATR3 Sarah Leigh Classified gene: HEATR3 as Amber List (moderate evidence)
Limb disorders v2.81 HEATR3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb disorders v2.81 HEATR3 Sarah Leigh Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.80 HEATR3 Sarah Leigh Entity copied from Rare anaemia v1.42
Limb disorders v2.80 HEATR3 Sarah Leigh gene: HEATR3 was added
gene: HEATR3 was added to Limb disorders. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: HEATR3.
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh Entity copied from Rare anaemia v1.42
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh gene: HEATR3 was added
gene: HEATR3 was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: HEATR3.
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
White matter disorders and cerebral calcification - childhood onset v1.244 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Fetal hydrops v1.55 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Intellectual disability v3.1702 HEATR3 Sarah Leigh Classified gene: HEATR3 as Amber List (moderate evidence)
Intellectual disability v3.1702 HEATR3 Sarah Leigh Added comment: Comment on list classification: The amber rating reflects that mild ID has been associated with HEATR3 variants.
Intellectual disability v3.1702 HEATR3 Sarah Leigh Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1701 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Early onset or syndromic epilepsy v2.590 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Severe microcephaly v2.317 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Dystonia, chorea or related movement disorder, childhood onset v1.258 XK Sarah Leigh Classified gene: XK as Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.258 XK Sarah Leigh Added comment: Comment on list classification: Not appropriate for this panel, as older onset.
Dystonia, chorea or related movement disorder, childhood onset v1.258 XK Sarah Leigh Gene: xk has been classified as Red List (Low Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh Tag Q3_22_rating was removed from gene: XK.
Tag Q3_22_MOI was removed from gene: XK.
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh edited their review of gene: XK: Changed rating: RED
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK would be predictive of possible future conditions.; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK could be predictive of possible future conditions.
Early onset dystonia v1.127 XK Sarah Leigh reviewed gene: XK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK would be predictive of possible future conditions.
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh Deleted their comment
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh Deleted their comment
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh Added comment: Comment on publications: 11761473;8004674;11032622;11261514;33652783;30128557;8619554
Dystonia, chorea or related movement disorder, childhood onset v1.257 XK Sarah Leigh Publications for gene: XK were set to 11761473; 30128557; 8004674; 8619554
Early onset dystonia v1.127 XK Sarah Leigh Publications for gene: XK were set to 11761473; 8004674; 11032622; 11261514
Early onset dystonia v1.126 XK Sarah Leigh Publications for gene: XK were set to 11761473; 11761473
Fetal anomalies v1.968 SETD2 Arina Puzriakova Classified gene: SETD2 as Amber List (moderate evidence)
Fetal anomalies v1.968 SETD2 Arina Puzriakova Added comment: Comment on list classification: Following clinical review, it was agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.968 SETD2 Arina Puzriakova Gene: setd2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.967 SETD2 Arina Puzriakova Mode of pathogenicity for gene: SETD2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v1.966 SETD2 Arina Puzriakova Phenotypes for gene: SETD2 were changed from SETD2-associated Overgrowth Syndrome to microcephaly; profound intellectual disability; congenital anomalies; dysmorphic facial features
Fetal anomalies v1.965 SETD2 Arina Puzriakova Publications for gene: SETD2 were set to
Fetal anomalies v1.964 SETD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SETD2.
Tag Q3_22_NHS_review tag was added to gene: SETD2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 IFNAR2 Arina Puzriakova Classified gene: IFNAR2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 IFNAR2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 IFNAR2 Arina Puzriakova Gene: ifnar2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.576 IFNAR2 Arina Puzriakova Publications for gene: IFNAR2 were set to 32048120; 26424569; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.575 IFNAR2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: IFNAR2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.575 IFNAR2 Arina Puzriakova reviewed gene: IFNAR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26424569, 33193576, 33544838, 35442417, 35944424; Phenotypes: Immunodeficiency 45, OMIM:616669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.590 XK Sarah Leigh edited their review of gene: XK: Added comment: After consultation with Helen Brittain (Clinical Fellow, Genomics England), the recommendation for XK has been changed to Amber. This is because there appear to be adult onset of neurological symptoms, including seizures. The scope of the Genetic epilepsy syndromes panel is targeting early onset severe or syndromic epilepsy.; Changed rating: AMBER
Arthrogryposis v3.163 ADAMTS15 Sarah Leigh Classified gene: ADAMTS15 as Amber List (moderate evidence)
Arthrogryposis v3.163 ADAMTS15 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Arthrogryposis v3.163 ADAMTS15 Sarah Leigh Gene: adamts15 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.162 ADAMTS15 Sarah Leigh gene: ADAMTS15 was added
gene: ADAMTS15 was added to Arthrogryposis. Sources: Literature
Q3_22_rating, Q3_22_MOI tags were added to gene: ADAMTS15.
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to 35962790
Phenotypes for gene: ADAMTS15 were set to distal arthrogryposis
Review for gene: ADAMTS15 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants have been reported by PMID: 35962790 in four independent consanguineous families, the unaffected parents were heterozgous for the causative variants in each of the families.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.575 IFNAR2 Arina Puzriakova Phenotypes for gene: IFNAR2 were changed from Defects in Intrinsic and Innate Immunity; Severe viral infections (disseminated vaccine-strain measles, HHV6); ?Immunodeficiency 45, 616669 to Immunodeficiency 45, OMIM:616669
Early onset dystonia v1.125 HPRT1 Sarah Leigh Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, OMIM:300322; Dystonia to Lesch-Nyhan syndrome, OMIM:300322
Early onset or syndromic epilepsy v2.590 CACNA1A Hannah Robinson reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36063114, PMID: 34267336, PMID: 33445191, PMID: 27250579; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset dystonia v1.124 HPRT1 Sarah Leigh Classified gene: HPRT1 as Green List (high evidence)
Early onset dystonia v1.124 HPRT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. Numous variants have been reported in Lesch-Nyhan syndrome (OMIM:300322) cases.
Early onset dystonia v1.124 HPRT1 Sarah Leigh Gene: hprt1 has been classified as Green List (High Evidence).
Early onset dystonia v1.123 HPRT1 Sarah Leigh Publications for gene: HPRT1 were set to
Intellectual disability v3.1701 ERMARD Dmitrijs Rots reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1701 SMAD3 Dmitrijs Rots reviewed gene: SMAD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.590 CAPRIN1 Konstantinos Varvagiannis gene: CAPRIN1 was added
gene: CAPRIN1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925; 35977029; 28135719; 31398340; https://doi.org/10.1101/2021.12.20.21267194
Phenotypes for gene: CAPRIN1 were set to Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures
Penetrance for gene: CAPRIN1 were set to Incomplete
Review for gene: CAPRIN1 was set to AMBER
Added comment: A cohort of 12 individuals harboring pathogenic CAPRIN1 variants is described in a recent report by Pavinato et al (2022 - PMID: 35979925).

DD, impaired speech/language development (100%), ID (83%), ASD (67%) and seizures (33%) are part of the phenotype (details below).

Enrichment for de novo LGD but also missense variants has also been demonstrated upon meta-analysis of different cohorts of 40,853 individuals with ID (N=31,625) or ASD (N=9,228) as discussed by Jia et al (2022 - PMID: 35977029).

Role of the gene:
Evidence supports among others, a role for CAPRIN1 in formation RNA-protein (stress) granules through interaction with other relevant proteins (e.g. G3BP1/2, FMRP) and regulation of gene expression (Pavinato et al - PMID: 35979925, Jia et al - PMID: 35977029).
Jia et al further demonstrated significant reduction of stress granule formation in CAPRIN1 KO HeLa lines.
Following generation of CAPRIN1+/- hiPSC line using CRISPR/Cas9 and differentiation into cortical neurons, Pavinato et al noted, altered neuronal structure, abnormal firing properties as well as increased neuronal degeneration possibly linked to presence of increased Ca+2 signals and increase in reactive oxygen species (ROS). Global de novo protein synthesis in neurons appeared to be impaired.

Variant type and inheritance :
All individuals reported by Paviato et al harbored pLoF (nonsense, frameshift, splicing and a synonymous variant resulting in abnormal splicing) variants. In most cases variants occurred de novo with the exception of 2 subjects having inherited pLoF variants from their affected/unaffected parent. Expressive variability, reduced penetrance and possibility of - a yet to be proven - sex bias are discussed (9M/3F).
Missense variants and enrichment for dn missense SNVs have also been shown in large cohorts. The impact of p.I373K has been studied.

Variant effect:
pLoF : Pavinato et al demonstrated reduced mRNA and protein levels for the truncating variants, and out-of frame exon skipping for a variant affecting splice donor site and a further SNV affecting the last nucleotide of ex8.
Missense SNVs : p.I373K abolished interaction with G3BP1/2 and disrupted stress granule formation in the study by Jia et al demonstrating a role of stress granules in pathogenesis of neurodevelopmental disorders.

Animal model:
As discussed by Pavinato et al abnormal neuronal structure and firing properties are observed in htz mouse models. Htz mice display features of ASD, difficulties in reversal learning (for ID), sporadic occurrence of seizures. Hearing impairment (as in 2-3 individuals described) due to reduced protection from noise exposure was reported in an ear-conditional ko model.

The report by Pavinato et al is summarized below.

For the study by Jia et al a summary can by found under the review of UBAP2L.

Reports of individuals in the context of larger cohorts were not here reviewed (eg. DDD study 2017, PMID: 28135719 || Ruzzo et al 2019, PMID: 31398340 || Fu et al 2021, https://doi.org/10.1101/2021.12.20.21267194).

----

Pavinato et al (2022 - PMID: 35979925) describe the phenotype associated with heterozygous CAPRIN1 pathogenic variants.

Overlapping features incl. impaired speech/language development (100%), ID (83%), ASD (67%), ADHD (82%), seizures (33% or 4/12 : absence seizures in 2, infantile spasms with absence epilepsy, secondary generalized epileptic seizures during sleep). Respiratory problems (50%), limb/skeletal anomalies (50%), feeding difficulties (33%), mild hearing hearing impairment (in 2 or 3). There was no evident dysmorphism, despite few recurrent features.

CAPRIN1 encodes cell cycle-associated protein 1. As the authors discuss, the gene is ubiquitously expressed with high expression in brain. The protein is known to interact with other RNA-binding proteins (eg. FMRP, G3BP1) for the formation of ribonucleoparticles / RNA granules. The gene localizes in neuronal RNA granules in dendrites. Previous studies have demonstrated a role in regulation of mRNA translation (acting as translational inhibitor with its overexpression leading to reduced protein synthesis). CAPRIN1 interacts with FMRP and CYFIP1, both also involved in regulation of mRNA translation.

One individual with microdeletion (~1.4 Mb spanning 8 genes with CAPRIN1 the only predicted to be haploinsufficient) as well as 11 additional subjects with nonsense/splicing variants were identified, following CMA, ES or GS. [The gene has a pHaplo of 0.98 and pLI of 0.97 (LOEUF 0.31)].

Variants were mostly de novo, although one individual had inherited a nonsense variant from his affected father while one further from her unaffected mother.

qRT-PCR showed reduced mRNA levels in patient fibroblasts and PBMCs while cycloheximide treatment in fibroblasts resulted in partial rescue in expression of mutant allele. Western blot in fibroblasts confirmed reduced protein levels.

cDNA analysis revealed that c.279+1G>T variant resulted in out-of-frame skipping of ex3, while c.879G>A (last base of ex8) resulted in out-of-frame skipping of ex8 and degradation by NMD, with cycloheximide restoring expression of mutant allele. [ NM_005898.5 ]

The authors generated a CAPRIN1+/- hiPSC line using CRISPR/Cas9 and hiPSCs were differentiated into cortical neurons. Htz immature neurons displayed altered neuronal structure, accompanied by reduced neurite length similar to previous observations in mice.

Increased neuronal degeneration was observed. Ca+2 signals (described in literature to trigger or contribute to neuronal death) were increased compared to controls. Increase in reactive oxygen species (ROS) following Ca+2 overload was also demonstrated, likely contributing to neuronal death.

Given the gene's role in regulation of mRNA translation, the authors assessed global de novo protein synthesis in neurons based on pyromicin incorporation (SUnSET assay) with findings supporting the impact of CAPRIN1 haploinsufficiency.

Heterozygous neurons were shown to display abnormal firing properties similar to a previously reported mouse model.

Mouse model : apart from the findings discussed above (abnormal neuronal structure and firing properties), heterozygous mice displayed similar features to the cohort described eg. reduced sociability and weaker preference for social novelty (as in ASD), difficulties in reversal learning (for ID), sporadic occurrence of seizures upon Morris water maze/contextual fearing tests and epileptic-like fEPSP after LTP. Breathing problems were noted in Carpin1-/- mice. Ear conditional ko was associated with early-onset progressive hearing loss and reduced protection from noise exposure which might be in line with few individuals with hearing impairment.
Sources: Literature
Intellectual disability v3.1701 CAPRIN1 Konstantinos Varvagiannis reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979925, 35977029, 28135719, 31398340, https://doi.org/10.1101/2021.12.20.21267194; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Autistic behavior, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.590 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to AMBER
Added comment: Seizures have been reported in several individuals although a formal diagnosis of epilepsy was retained in ~30% in a small cohort discussed below. Consider inclusion with amber rating.

-----

Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

--------

Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Intellectual disability v3.1701 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

--------

Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Fetal anomalies v1.964 SETD2 Rhiannon Mellis reviewed gene: SETD2: 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: PMID: 32710489, 33255631; Phenotypes: microcephaly, profound intellectual disability, congenital anomalies, dysmorphic facial features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v1.132 KIAA0556 Samantha Malka gene: KIAA0556 was added
gene: KIAA0556 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: KIAA0556 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0556 were set to PMID: 32164589
Phenotypes for gene: KIAA0556 were set to Joubert syndrome 26
Penetrance for gene: KIAA0556 were set to Complete
Mode of pathogenicity for gene: KIAA0556 was set to Other
Review for gene: KIAA0556 was set to RED
Added comment: Niceta et al (2020) - published a case including coloboma with a patient with biallelic KIAA0556 mutations (patient also had biallelic mutations in KIF7)
Sources: Literature
Structural eye disease v1.132 KIF7 Samantha Malka Deleted their comment
Structural eye disease v1.132 KIF7 Samantha Malka commented on gene: KIF7: Niceta et al (2020) - published a case including coloboma with a patient with biallelic KIF7 mutations (patient also had biallelic mutations in KIAA0556)
Structural eye disease v1.132 KIF7 Samantha Malka reviewed gene: KIF7: Rating: RED; Mode of pathogenicity: Other; Publications: PMID: 32164589; Phenotypes: Joubert syndrome 12; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.132 EP300 Samantha Malka gene: EP300 was added
gene: EP300 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: EP300 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EP300 were set to PMID: 26279656
Phenotypes for gene: EP300 were set to Rubinstein-Taybi syndrome 2
Penetrance for gene: EP300 were set to unknown
Mode of pathogenicity for gene: EP300 was set to Other
Review for gene: EP300 was set to RED
Added comment: One reported case of Rubinstein-Taybi syndrome 2 with an EP300 genetic diagnosis, having a phenotype including coloboma.
Sources: Literature
Structural eye disease v1.132 NR2F1 Samantha Malka gene: NR2F1 was added
gene: NR2F1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: NR2F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR2F1 were set to PMID: 34787370
Phenotypes for gene: NR2F1 were set to Bosch-Boonstra-Schaaf optic atrophy syndrome
Penetrance for gene: NR2F1 were set to Complete
Mode of pathogenicity for gene: NR2F1 was set to Other
Review for gene: NR2F1 was set to RED
Added comment: One report in literature of a phenotype including coloboma
Sources: Literature
Intellectual disability v3.1701 ANK3 Rachel Challis reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28687526, 34218362; Phenotypes: Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova commented on gene: RPS15: This gene has been flagged for GMS expert review as published evidence linking germline variants to haematological malignancies is limited, which may warrant a rating downgrade from Green, subject to review.
RPS15 somatic variants are enriched within chronic lymphocytic leukemia, particularly in aggressive cases - however, the contribution of germline variants is not well-defined.
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova Tag somatic tag was added to gene: RPS15.
Haematological malignancies for rare disease v1.14 RPS15 Arina Puzriakova Tag somatic tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova Tag Q3_22_rating tag was added to gene: RPS15.
Tag Q3_22_expert_review tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova Phenotypes for gene: RPS15 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML; Osteosarcoma, soft tissue sarcomas to Diamond-Blackfan anemia; Chronic lymphocytic leukemia
Haematological malignancies for rare disease v1.14 RPS15 Arina Puzriakova Phenotypes for gene: RPS15 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML; Osteosarcoma, soft tissue sarcomas to Diamond-Blackfan anemia; Chronic lymphocytic leukemia
Haematological malignancies cancer susceptibility v2.35 RPS15 Arina Puzriakova Publications for gene: RPS15 were set to 28297620
Haematological malignancies for rare disease v1.13 RPS15 Arina Puzriakova Publications for gene: RPS15 were set to 28297620
Haematological malignancies for rare disease v1.12 RPS15 Arina Puzriakova Tag watchlist tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.34 RPS15 Arina Puzriakova reviewed gene: RPS15: Rating: ; Mode of pathogenicity: None; Publications: 19061985, 26466571, 26675346, 30181176, 34251413; Phenotypes: Diamond-Blackfan anemia, Chronic lymphocytic leukemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haematological malignancies for rare disease v1.12 RPS15 Arina Puzriakova reviewed gene: RPS15: Rating: ; Mode of pathogenicity: None; Publications: 19061985, 26466571, 26675346, 30181176, 34251413; Phenotypes: Diamond-Blackfan anemia, Chronic lymphocytic leukemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia, adult onset v2.158 STUB1 James Polke reviewed gene: STUB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32713943, 33564152, 35493319, 34906452; Phenotypes: Cerebellar Ataxia, Dementia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Neurodegenerative disorders, adult onset v2.284 STUB1 James Polke reviewed gene: STUB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32713943, 33564152, 35493319, 34906452; Phenotypes: Cerebellar Ataxia, Dementia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.284 STUB1 James Polke Deleted their review
Neurodegenerative disorders, adult onset v2.284 STUB1 James Polke reviewed gene: STUB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32713943, 33564152; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.24 FASTKD2 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: FASTKD2.
Mitochondrial disorder with complex IV deficiency v1.24 FASTKD2 Arina Puzriakova Publications for gene: FASTKD2 were set to 28499982
Mitochondrial disorder with complex IV deficiency v1.23 FASTKD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: FASTKD2.
Mitochondrial disorder with complex IV deficiency v1.23 FASTKD2 Arina Puzriakova reviewed gene: FASTKD2: Rating: RED; Mode of pathogenicity: None; Publications: 31944455; Phenotypes: Combined oxidative phosphorylation deficiency 44, OMIM:618855; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.148 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.148 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Hereditary spastic paraplegia, childhood onset v2.148 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.147 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
Optic neuropathy v2.75 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Optic neuropathy v2.75 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Optic neuropathy v2.75 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.74 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
White matter disorders and cerebral calcification - childhood onset v1.244 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.244 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that a Green rating on this panel is justified given the number of unrelated families presenting a relevant phenotype meets the criteria.
White matter disorders and cerebral calcification - childhood onset v1.244 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that a Green rating on this panel is justified given the number of unrelated families presenting a relevant phenotype meets the criteria.
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.243 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
Tag Q3_22_rating tag was added to gene: BLOC1S1.
Intellectual disability v3.1700 BLOC1S1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: BLOC1S1.
Optic neuropathy v2.74 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Optic neuropathy v2.74 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Optic neuropathy. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Hereditary spastic paraplegia, childhood onset v2.147 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Hereditary spastic paraplegia, childhood onset v2.147 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
White matter disorders and cerebral calcification - childhood onset v1.243 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
White matter disorders and cerebral calcification - childhood onset v1.243 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Early onset or syndromic epilepsy v2.589 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Early onset or syndromic epilepsy v2.589 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Genetic epilepsy syndromes. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Intellectual disability v3.1700 BLOC1S1 Arina Puzriakova Publications for gene: BLOC1S1 were updated from PMID: 33875846 to 33875846
Early onset or syndromic epilepsy v2.588 FASTKD2 Arina Puzriakova Publications for gene: FASTKD2 were set to
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: FASTKD2.
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova reviewed gene: FASTKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18771761, 28499982, 31944455, 35729327; Phenotypes: Combined oxidative phosphorylation deficiency 44, OMIM:618855; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, adult onset v1.174 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.256 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855; Dystonia
Dystonia, chorea or related movement disorder, childhood onset v1.255 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Dystonia
Dystonia, chorea or related movement disorder, childhood onset v1.254 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.79 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from ?Mitochondrial complex IV deficiency, 220110 to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Mitochondrial disorders v2.177 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Dystonia, chorea or related movement disorder, adult onset v1.173 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855; Dystonia
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Early onset or syndromic epilepsy v2.586 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.319 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors) to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Possible mitochondrial disorder, nuclear genes v1.160 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from ?Mitochondrial complex IV deficiency, 220110 to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Undiagnosed metabolic disorders v1.562 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Neurodegenerative disorders, adult onset v2.284 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Neurodegenerative disorders, adult onset v2.283 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.23 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from ?Mitochondrial complex IV deficiency, 220110 to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Early onset dystonia v1.122 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.121 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855; Dystonia
Likely inborn error of metabolism v2.318 UQCRC2 Arina Puzriakova Mode of inheritance for gene: UQCRC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.317 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Mitochondrial disorders v2.176 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Possible mitochondrial disorder, nuclear genes v1.159 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Mitochondrial disorder with complex III deficiency v1.17 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Mitochondrial disorders v2.175 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Isolated complex III deficiency; Mitochondrial complex III deficiency, nuclear type 5, 615160 to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Likely inborn error of metabolism v2.316 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Mitochondrial complex III deficiency, nuclear type 5, 615160; Isolated complex III deficiency to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Possible mitochondrial disorder, nuclear genes v1.158 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Mitochondrial complex III deficiency, nuclear type 5, 615160 to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Mitochondrial disorder with complex III deficiency v1.16 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Mitochondrial complex III deficiency, nuclear type 5, 615160 to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Likely inborn error of metabolism v2.315 UQCRC1 Arina Puzriakova Classified gene: UQCRC1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.315 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804)
Likely inborn error of metabolism v2.315 UQCRC1 Arina Puzriakova Gene: uqcrc1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.174 UQCRC1 Arina Puzriakova Classified gene: UQCRC1 as Amber List (moderate evidence)
Mitochondrial disorders v2.174 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804)
Mitochondrial disorders v2.174 UQCRC1 Arina Puzriakova Gene: uqcrc1 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.282 UQCRC1 Arina Puzriakova Tag watchlist tag was added to gene: UQCRC1.
Neurodegenerative disorders, adult onset v2.282 UQCRC1 Arina Puzriakova Classified gene: UQCRC1 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.282 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804)
Neurodegenerative disorders, adult onset v2.282 UQCRC1 Arina Puzriakova Gene: uqcrc1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.314 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Neurodegenerative disorders, adult onset v2.281 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to 33141179; 33248804
Mitochondrial disorders v2.173 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Possible mitochondrial disorder, nuclear genes v1.157 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Mitochondrial disorder with complex III deficiency v1.15 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to 30788857; 33141179; 33779694; 33248804
Mitochondrial disorder with complex III deficiency v1.14 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Likely inborn error of metabolism v2.313 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.172 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder, nuclear genes v1.156 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.312 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Mitochondrial disorder with complex III deficiency v1.13 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.171 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Neurodegenerative disorders, adult onset v2.280 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from 33141179; 33248804 to Parkinsonism with polyneuropathy, OMIM:619279
Possible mitochondrial disorder, nuclear genes v1.155 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Mitochondrial disorder with complex III deficiency v1.12 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Likely inborn error of metabolism v2.311 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from lesions in the medulla oblongata to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Mitochondrial disorders v2.170 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Mitochondrial disorder with complex IV deficiency v1.22 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Possible mitochondrial disorder, nuclear genes v1.154 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Likely inborn error of metabolism v2.310 NFS1 Arina Puzriakova Classified gene: NFS1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.310 NFS1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS review - associated with relevant phenotype in OMIM (MIM#619386) but not yet in G2P. At least one variant reported in six cases from two unrelated families, together with supportive functional studies.
Likely inborn error of metabolism v2.310 NFS1 Arina Puzriakova Gene: nfs1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.309 NFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NFS1.
Likely inborn error of metabolism v2.309 NFS1 Arina Puzriakova reviewed gene: NFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24498631, 33457206; Phenotypes: Combined oxidative phosphorylation deficiency 52, OMIM: 619386; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.309 NFS1 Arina Puzriakova Mode of inheritance for gene: NFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.153 NFS1 Arina Puzriakova Classified gene: NFS1 as Amber List (moderate evidence)
Possible mitochondrial disorder, nuclear genes v1.153 NFS1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS review - associated with relevant phenotype in OMIM (MIM#619386) but not yet in G2P. At least one variant reported in six cases from two unrelated families, together with supportive functional studies.
Possible mitochondrial disorder, nuclear genes v1.153 NFS1 Arina Puzriakova Gene: nfs1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.308 NFS1 Arina Puzriakova Publications for gene: NFS1 were set to
Possible mitochondrial disorder, nuclear genes v1.152 NFS1 Arina Puzriakova Publications for gene: NFS1 were set to 24498631
Possible mitochondrial disorder, nuclear genes v1.151 NFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NFS1.
Possible mitochondrial disorder, nuclear genes v1.151 NFS1 Arina Puzriakova edited their review of gene: NFS1: Added comment: Also now additional paper - PMID 33457206: reporting a second family (consanguineous) with three affected children and supportive functional data. Homozygous for the same missense variant as reported in the 2014 paper - this family of Christian Arab descent; the family in the previous report of Mennonite background. Suggests this is a mutation hotspot.; Changed rating: GREEN; Changed publications to: 24498631, 33457206
Possible mitochondrial disorder, nuclear genes v1.151 NFS1 Arina Puzriakova changed review comment from: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on current evidence.; to: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on evidence provided in PMID:24498631
Likely inborn error of metabolism v2.307 NFS1 Arina Puzriakova Phenotypes for gene: NFS1 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 52, OMIM:619386
Mitochondrial disorders v2.169 NFS1 Arina Puzriakova Phenotypes for gene: NFS1 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 52, OMIM:619386
Possible mitochondrial disorder, nuclear genes v1.151 NFS1 Arina Puzriakova Phenotypes for gene: NFS1 were changed from Infantile mitochondrial complex II/III deficiency to Combined oxidative phosphorylation deficiency 52, OMIM:619386
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 IRF7 Dmitrijs Rots reviewed gene: IRF7: Rating: AMBER; Mode of pathogenicity: None; Publications: 35986347; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 IFNAR2 Dmitrijs Rots changed review comment from: In review 35986347 report on family with severe COVID and biallelic IFNAR2 variant.; to: In review 35986347 report on study + family with severe COVID and biallelic IFNAR2 variant.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 IFNAR2 Dmitrijs Rots reviewed gene: IFNAR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35986347; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.168 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Likely inborn error of metabolism v2.306 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA Depletion Syndrome (biallelic); Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Undiagnosed metabolic disorders v1.561 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Mitochondrial liver disease v1.8 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, 609286 to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Possible mitochondrial disorder, nuclear genes v1.150 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, 609286 to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Mitochondrial DNA maintenance disorder v1.24 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, 609286 to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.25 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Hereditary Paraganglioma-Pheochromocytoma Syndrome; Leigh syndrome, 256000Mitochondrial respiratory chain complex II deficiency, 252011Cardiomyopathy, dilated, 1GG, 613642Paragangliomas 5, 614165 to Paragangliomas 5, OMIM:614165
Inherited phaeochromocytoma and paraganglioma v1.11 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Leigh syndrome, 256000Mitochondrial respiratory chain complex II deficiency, 252011Cardiomyopathy, dilated, 1GG, 613642Paragangliomas 5, 614165; Hereditary Paraganglioma-Pheochromocytoma Syndrome to Paragangliomas 5, OMIM:614165
Neuroendocrine cancer pertinent cancer susceptibility v1.4 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Neuroendocrine cancer to Paragangliomas 5, OMIM:614165
Likely inborn error of metabolism v2.305 SDHA Arina Puzriakova Publications for gene: SDHA were set to 27604308
Undiagnosed metabolic disorders v1.560 SDHA Arina Puzriakova Publications for gene: SDHA were set to 27604308
Mitochondrial disorders v2.167 SDHA Arina Puzriakova Publications for gene: SDHA were set to
Possible mitochondrial disorder, nuclear genes v1.149 SDHA Arina Puzriakova Publications for gene: SDHA were set to
Likely inborn error of metabolism v2.304 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Leigh syndrome, 256000; Paragangliomas 5, 614165; Cardiomyopathy, dilated, 1GG, 613642; Isolated complex II deficiency; Mitochondrial respiratory chain complex II deficiency, 252011; Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Mitochondrial disorder with complex II deficiency v1.9 SDHA Arina Puzriakova Publications for gene: SDHA were set to
Undiagnosed metabolic disorders v1.559 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex II deficiency; Leigh syndrome, 256000; Mitochondrial respiratory chain complex II deficiency, 252011; Cardiomyopathy, dilated, 1GG, 613642; Paragangliomas 5, 614165; Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Mitochondrial disorders v2.166 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Isolated complex II deficiency; Leigh syndrome, 256000; Mitochondrial respiratory chain complex II deficiency, 252011; Cardiomyopathy, dilated, 1GG, 613642; Paragangliomas 5, 614165; Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Possible mitochondrial disorder, nuclear genes v1.148 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, 252011; Leigh syndrome, 256000 to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Mitochondrial disorder with complex II deficiency v1.8 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, 252011; Leigh syndrome, 256000 to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Likely inborn error of metabolism v2.303 QRSL1 Arina Puzriakova Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835 to Combined oxidative phosphorylation deficiency 40, OMIM:618835
Mitochondrial disorders v2.165 QRSL1 Arina Puzriakova Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835 to Combined oxidative phosphorylation deficiency 40, OMIM:618835
Likely inborn error of metabolism v2.302 QRSL1 Arina Puzriakova Publications for gene: QRSL1 were set to 29440775; 26741492
Possible mitochondrial disorder, nuclear genes v1.147 QRSL1 Arina Puzriakova Phenotypes for gene: QRSL1 were changed from Mitochondrial cardiomyopathy; Combined oxidative phosphorylation deficiency 40, 618835 to Combined oxidative phosphorylation deficiency 40, OMIM:618835
Mitochondrial disorders v2.164 QRSL1 Arina Puzriakova Publications for gene: QRSL1 were set to 29440775; 26741492
Possible mitochondrial disorder, nuclear genes v1.146 QRSL1 Arina Puzriakova Publications for gene: QRSL1 were set to 30283131; 26741492
Early onset or syndromic epilepsy v2.585 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Fetal anomalies v1.964 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16 (hepatic type), MONDO:0032799; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MONDO:0012415 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Likely inborn error of metabolism v2.301 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 27604308
Mitochondrial liver disease v1.7 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 30157269
Possible mitochondrial disorder, nuclear genes v1.145 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 30157269
Mitochondrial DNA maintenance disorder v1.23 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 30157269
Mitochondrial disorders v2.163 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Likely inborn error of metabolism v2.300 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Disorders of mitochondrial DNA maintenance and integrity; Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Undiagnosed metabolic disorders v1.558 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Mitochondrial liver disease v1.6 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome, NA; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Possible mitochondrial disorder, nuclear genes v1.144 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome, NA; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Mitochondrial DNA maintenance disorder v1.22 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome, NA; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Dystonia, chorea or related movement disorder, childhood onset v1.253 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Intellectual disability v3.1699 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Early onset or syndromic epilepsy v2.584 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Cytopenia - NOT Fanconi anaemia v1.72 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Likely inborn error of metabolism v2.299 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Undiagnosed metabolic disorders v1.557 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Mitochondrial disorders v2.162 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Possible mitochondrial disorder, nuclear genes v1.143 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Possible mitochondrial disorder, nuclear genes v1.142 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510; 25597511; 25650066; 26916670; 28687938; 34140661
Cytopenia - NOT Fanconi anaemia v1.71 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510; 25597511; 25650066; 26916670; 28687938; 34140661
Likely inborn error of metabolism v2.298 UQCRFS1 Arina Puzriakova Classified gene: UQCRFS1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.298 UQCRFS1 Arina Puzriakova Gene: uqcrfs1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.161 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Mitochondrial disorders v2.160 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Likely inborn error of metabolism v2.297 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Likely inborn error of metabolism v2.296 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Possible mitochondrial disorder, nuclear genes v1.141 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Mitochondrial disorder with complex III deficiency v1.11 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Mitochondrial disorders v2.159 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.140 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Mitochondrial disorder with complex III deficiency v1.10 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Likely inborn error of metabolism v2.295 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex III deficiency v1.9 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.158 UQCRFS1 Arina Puzriakova Classified gene: UQCRFS1 as Amber List (moderate evidence)
Mitochondrial disorders v2.158 UQCRFS1 Arina Puzriakova Gene: uqcrfs1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder, nuclear genes v1.139 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.157 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to 28604674
Likely inborn error of metabolism v2.294 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to 28604674
Possible mitochondrial disorder, nuclear genes v1.138 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to
Mitochondrial disorders v2.156 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Likely inborn error of metabolism v2.293 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Possible mitochondrial disorder, nuclear genes v1.137 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Mitochondrial disorder with complex I deficiency v1.30 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Mitochondrial disorder with complex I deficiency v1.29 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to 28604674
Likely inborn error of metabolism v2.292 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Mitochondrial disorders v2.155 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Possible mitochondrial disorder, nuclear genes v1.136 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Mitochondrial DNA maintenance disorder v1.21 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Mitochondrial disorders v2.154 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Mitochondrial liver disease v1.5 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from MITOCHONDRIAL DNA DEPLETION SYNDROME 15 (HEPATOCEREBRAL TYPE), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Likely inborn error of metabolism v2.291 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Possible mitochondrial disorder, nuclear genes v1.135 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Mitochondrial DNA maintenance disorder v1.20 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Mitochondrial disorders v2.153 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398 to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Likely inborn error of metabolism v2.290 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398 to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Possible mitochondrial disorder, nuclear genes v1.134 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398 to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Dystonia, chorea or related movement disorder, childhood onset v1.252 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Possible mitochondrial disorder, nuclear genes v1.133 TARS2 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: TARS2.
Inherited white matter disorders v1.160 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Mitochondrial Leukoencephalopathy; Succinate dehydrogenase-deficient leukoencephalopathy; complex II deficiency to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
White matter disorders and cerebral calcification - childhood onset v1.242 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Succinate dehydrogenase-deficient leukoencephalopathy; complex II deficiency; Mitochondrial Leukoencephalopathy to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Childhood solid tumours v2.35 SDHB Arina Puzriakova Mode of inheritance for gene: SDHB was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult solid tumours cancer susceptibility v2.22 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Familial Paraganglioma and Pheochromocytoma to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864; Gastrointestinal stromal tumor, OMIM:606764
Childhood solid tumours v2.34 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 2, 612359; Gastrointestinal stromal tumor, 606764 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864; Gastrointestinal stromal tumor, OMIM:606764
Adult solid tumours for rare disease v1.34 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Familial Paraganglioma and Pheochromocytoma to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864; Gastrointestinal stromal tumor, OMIM:606764
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.24 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paraganglioma and Gastric Stromal Sarcoma; Paragangliomas 4, 115310Pheochromocytoma, 171300Paraganglioma and gastric stromal sarcoma, 606864Cowden syndrome 2, 612359Gastrointestinal stromal tumor, 606764 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Inherited phaeochromocytoma and paraganglioma v1.10 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paraganglioma and Gastric Stromal Sarcoma; Paragangliomas 4, 115310Pheochromocytoma, 171300Paraganglioma and gastric stromal sarcoma, 606864Cowden syndrome 2, 612359Gastrointestinal stromal tumor, 606764 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Multiple endocrine tumours v1.14 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Endocrine Cancer; familial paraganglioma to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Inherited renal cancer v1.22 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paragangliomas 4, OMIM:115310; Renal cell carcinoma (disease), MONDO:0005086 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Renal cancer pertinent cancer susceptibility v1.2 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Renal cancer to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Neuroendocrine cancer pertinent cancer susceptibility v1.3 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Neuroendocrine cancer to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Genodermatoses with malignancies v1.7 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 2, 612359; Gastrointestinal stromal tumor, 606764 to Gastrointestinal stromal tumor, OMIM:606764; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Likely inborn error of metabolism v2.289 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Mitochondrial Diseases; Gastrointestinal stromal tumor, 606764; Pheochromocytoma, 171300; Paragangliomas 4, 115310; Isolated complex II deficiency; Cowden syndrome 2, 612359; Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Paraganglioma and gastric stromal sarcoma, 606864 to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Undiagnosed metabolic disorders v1.556 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex II deficiency; Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Gastrointestinal stromal tumor, 606764; Mitochondrial Diseases to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Mitochondrial disorders v2.152 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Isolated complex II deficiency; Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 2, 612359; Gastrointestinal stromal tumor, 606764; Mitochondrial Diseases to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Possible mitochondrial disorder, nuclear genes v1.133 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from No OMIM phenotype to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Mitochondrial disorder with complex II deficiency v1.7 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from No OMIM phenotype to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Mitochondrial disorders v2.151 SDHB Arina Puzriakova Publications for gene: SDHB were set to 26925370; 22972948
Possible mitochondrial disorder, nuclear genes v1.132 SDHB Arina Puzriakova Publications for gene: SDHB were set to 22972948
Mitochondrial disorder with complex II deficiency v1.6 SDHB Arina Puzriakova Publications for gene: SDHB were set to 22972948
Likely inborn error of metabolism v2.288 NSUN3 Arina Puzriakova Phenotypes for gene: NSUN3 were changed from Combined mitochondrial respiratory chain complex deficiency to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Mitochondrial disorders v2.150 NSUN3 Arina Puzriakova Phenotypes for gene: NSUN3 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Possible mitochondrial disorder, nuclear genes v1.131 NSUN3 Arina Puzriakova Phenotypes for gene: NSUN3 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Mitochondrial disorders v2.149 NSUN3 Arina Puzriakova Publications for gene: NSUN3 were set to 27356879
Likely inborn error of metabolism v2.287 NSUN3 Arina Puzriakova Publications for gene: NSUN3 were set to 27356879
Possible mitochondrial disorder, nuclear genes v1.130 NSUN3 Arina Puzriakova Publications for gene: NSUN3 were set to 27356879
Mitochondrial disorders v2.148 NDUFC2 Arina Puzriakova Publications for gene: NDUFC2 were set to
Mitochondrial disorders v2.147 NDUFC2 Arina Puzriakova Phenotypes for gene: NDUFC2 were changed from Isolated complex I deficiency; No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 36, OMIM:619170
Mitochondrial disorders v2.146 NDUFC2 Arina Puzriakova Classified gene: NDUFC2 as Amber List (moderate evidence)
Mitochondrial disorders v2.146 NDUFC2 Arina Puzriakova Gene: ndufc2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.145 NDUFC2 Arina Puzriakova Mode of inheritance for gene: NDUFC2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.129 SSBP1 Arina Puzriakova Classified gene: SSBP1 as Amber List (moderate evidence)
Possible mitochondrial disorder, nuclear genes v1.129 SSBP1 Arina Puzriakova Gene: ssbp1 has been classified as Amber List (Moderate Evidence).
Mitochondrial DNA maintenance disorder v1.19 SSBP1 Arina Puzriakova Classified gene: SSBP1 as Amber List (moderate evidence)
Mitochondrial DNA maintenance disorder v1.19 SSBP1 Arina Puzriakova Gene: ssbp1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder, nuclear genes v1.128 SSBP1 Arina Puzriakova Mode of pathogenicity for gene: SSBP1 was changed from Other to Other
Possible mitochondrial disorder, nuclear genes v1.127 SSBP1 Arina Puzriakova Publications for gene: SSBP1 were set to 29182774
Mitochondrial DNA maintenance disorder v1.18 SSBP1 Arina Puzriakova Publications for gene: SSBP1 were set to 29182774
Possible mitochondrial disorder, nuclear genes v1.126 SSBP1 Arina Puzriakova Phenotypes for gene: SSBP1 were changed from No OMIM phenotype to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Mitochondrial DNA maintenance disorder v1.17 SSBP1 Arina Puzriakova Phenotypes for gene: SSBP1 were changed from No OMIM phenotype to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Likely inborn error of metabolism v2.286 NDUFB10 Arina Puzriakova Classified gene: NDUFB10 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.286 NDUFB10 Arina Puzriakova Gene: ndufb10 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.285 NDUFB10 Arina Puzriakova Mode of inheritance for gene: NDUFB10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.144 NDUFB10 Arina Puzriakova Classified gene: NDUFB10 as Amber List (moderate evidence)
Mitochondrial disorders v2.144 NDUFB10 Arina Puzriakova Gene: ndufb10 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.284 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to
Mitochondrial disorders v2.143 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to 28040730
Possible mitochondrial disorder, nuclear genes v1.125 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to 28040730
Likely inborn error of metabolism v2.283 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from No OMIM phenotype; Isolated complex I deficiency to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Mitochondrial disorder with complex I deficiency v1.28 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to 28040730
Possible mitochondrial disorder, nuclear genes v1.124 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Mitochondrial disorders v2.142 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from Isolated complex I deficiency; No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Mitochondrial disorder with complex I deficiency v1.27 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Possible mitochondrial disorder, nuclear genes v1.123 NDUFB10 Arina Puzriakova changed review comment from: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; to: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. Three individuals from two unrelated families now reported with convincing functional studies that support mitochondrial disease (PMID: 28040730; 33169436)
Likely inborn error of metabolism v2.282 NDUFA8 Arina Puzriakova Classified gene: NDUFA8 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.282 NDUFA8 Arina Puzriakova Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.141 NDUFA8 Arina Puzriakova Classified gene: NDUFA8 as Amber List (moderate evidence)
Mitochondrial disorders v2.141 NDUFA8 Arina Puzriakova Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.281 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Mitochondrial Diseases; No OMIM phenotype; Isolated complex I deficiency to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Mitochondrial disorders v2.140 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Isolated complex I deficiency; No OMIM phenotype; Mitochondrial Diseases to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Likely inborn error of metabolism v2.280 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to
Possible mitochondrial disorder, nuclear genes v1.123 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272 to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Mitochondrial disorder with complex I deficiency v1.26 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272 to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Mitochondrial disorders v2.139 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to 15576045
Possible mitochondrial disorder, nuclear genes v1.122 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272
Mitochondrial disorder with complex I deficiency v1.25 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272
Likely inborn error of metabolism v2.279 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.138 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.121 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to
Possible mitochondrial disorder, nuclear genes v1.120 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.24 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to 15576045
Mitochondrial disorder with complex I deficiency v1.23 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.137 NDUFA13 Arina Puzriakova Classified gene: NDUFA13 as Amber List (moderate evidence)
Mitochondrial disorders v2.137 NDUFA13 Arina Puzriakova Gene: ndufa13 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.278 NDUFA13 Arina Puzriakova Classified gene: NDUFA13 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.278 NDUFA13 Arina Puzriakova Gene: ndufa13 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.277 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from Mitochondrial Diseases; {Thyroid carcinoma, Hurthle cell}, 607464; Isolated complex I deficiency to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Mitochondrial disorders v2.136 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from Isolated complex I deficiency; Mitochondrial Diseases; ?Mitochondrial complex I deficiency, nuclear type 28, 618249 to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Possible mitochondrial disorder, nuclear genes v1.119 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from ?Mitochondrial complex I deficiency, nuclear type 28, 618249 to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Mitochondrial disorder with complex I deficiency v1.22 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from ?Mitochondrial complex I deficiency, nuclear type 28, 618249 to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Likely inborn error of metabolism v2.276 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to 25901006
Mitochondrial disorders v2.135 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to 25901006
Possible mitochondrial disorder, nuclear genes v1.118 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to
Mitochondrial disorder with complex I deficiency v1.21 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to 25901006
Possible mitochondrial disorder, nuclear genes v1.117 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Intellectual disability v3.1698 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Likely inborn error of metabolism v2.275 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Dystonia, chorea or related movement disorder, adult onset v1.172 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23, 618244; Leigh syndrome due to mitochondrial complex 1 deficiency to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Mitochondrial disorders v2.134 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Neurodegenerative disorders, adult onset v2.279 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency 256000 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Mitochondrial disorder with complex I deficiency v1.20 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Intellectual disability v3.1697 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to
Likely inborn error of metabolism v2.274 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Dystonia, chorea or related movement disorder, adult onset v1.171 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Neurodegenerative disorders, adult onset v2.278 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Mitochondrial disorders v2.133 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 33715266
Possible mitochondrial disorder, nuclear genes v1.116 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to
Mitochondrial disorder with complex I deficiency v1.19 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Undiagnosed metabolic disorders v1.555 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Undiagnosed metabolic disorders v1.554 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Undiagnosed metabolic disorders v1.553 LYRM4 Arina Puzriakova Classified gene: LYRM4 as Green List (high evidence)
Undiagnosed metabolic disorders v1.553 LYRM4 Arina Puzriakova Gene: lyrm4 has been classified as Green List (High Evidence).
Mitochondrial disorders v2.132 LYRM4 Arina Puzriakova Classified gene: LYRM4 as Amber List (moderate evidence)
Mitochondrial disorders v2.132 LYRM4 Arina Puzriakova Gene: lyrm4 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.273 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Mitochondrial disorders v2.131 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Mitochondrial disorders v2.130 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to
Possible mitochondrial disorder, nuclear genes v1.115 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Likely inborn error of metabolism v2.272 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Possible mitochondrial disorder, nuclear genes v1.114 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Possible mitochondrial disorder, nuclear genes v1.113 COX6A2 Arina Puzriakova Publications for gene: COX6A2 were set to
Mitochondrial disorder with complex IV deficiency v1.21 COX6A2 Arina Puzriakova Publications for gene: COX6A2 were set to
Possible mitochondrial disorder, nuclear genes v1.112 COX6A2 Arina Puzriakova Mode of inheritance for gene: COX6A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.20 COX6A2 Arina Puzriakova Mode of inheritance for gene: COX6A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.111 COX6A2 Arina Puzriakova Phenotypes for gene: COX6A2 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Mitochondrial disorder with complex IV deficiency v1.19 COX6A2 Arina Puzriakova Phenotypes for gene: COX6A2 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Neurodegenerative disorders, adult onset v2.277 SPTLC1 James Polke gene: SPTLC1 was added
gene: SPTLC1 was added to Neurodegenerative disorders - adult onset. Sources: NHS GMS
Mode of inheritance for gene: SPTLC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTLC1 were set to 34059824; 34459874; 35627278; 35900868
Phenotypes for gene: SPTLC1 were set to Juvenile ALS
Penetrance for gene: SPTLC1 were set to Incomplete
Mode of pathogenicity for gene: SPTLC1 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: SPTLC1 was set to GREEN
Added comment: SPTLC1 previously associated with HSN1A but variants in these two publications associated with juvenile ALS. 34059824 and 35900868 propose a distinct pathomechanism of juvenile ALS variants (increased sphinganine systhesis) compared to HSN1A variants (shift to deoxysphinganine synthesis). At least 5 different variants now reported, almost all de-novo, but one family in 34059824 with p.Leu39del inherited from father with mild sensorimotor axonal neuropathy. Juvenile onset but inclusion on this adult panel in-line with current inclusion of ALS2 and SETX which also cause early onset ALS.

No evidence that LoF variants cause HSN1A or juvenile ALS - GOF mechanisms demonstrated.
Sources: NHS GMS
Likely inborn error of metabolism v2.271 ATP5G3 Arina Puzriakova Classified gene: ATP5G3 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.271 ATP5G3 Arina Puzriakova Gene: atp5g3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.129 ATP5G3 Arina Puzriakova Classified gene: ATP5G3 as Amber List (moderate evidence)
Mitochondrial disorders v2.129 ATP5G3 Arina Puzriakova Gene: atp5g3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.270 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.128 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.269 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Mitochondrial disorders v2.127 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Possible mitochondrial disorder, nuclear genes v1.110 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder, nuclear genes v1.109 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Mitochondrial disorder with complex V deficiency v1.15 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Mitochondrial disorders v2.126 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Likely inborn error of metabolism v2.268 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Possible mitochondrial disorder, nuclear genes v1.108 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Mitochondrial disorder with complex V deficiency v1.14 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Mitochondrial disorder with complex V deficiency v1.13 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.583 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22 616045; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Likely inborn error of metabolism v2.267 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to PMID: 23599390 (two siblings with a severe neonatal encephalopathy caused by complex V deficiency); PMID: 23596069 (newborn female with failure to thrive, microcephaly, encephalopathy, IUGR, hypotonia, bacteremia, pulmonary hypertension, heart failure, and mitchondrial depletion).
Mitochondrial disorders v2.125 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 23599390; 23596069
Likely inborn error of metabolism v2.266 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22; Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228; ?Combined oxidative phosphorylation deficiency 22 616045 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Mitochondrial disorder with complex V deficiency v1.12 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 23596069; 23599390
Mitochondrial disorders v2.124 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Mitochondrial disorder with complex V deficiency v1.11 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22, 616045; ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Possible mitochondrial disorder, nuclear genes v1.107 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22, 616045; ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Possible mitochondrial disorder, nuclear genes v1.106 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 23596069; 23599390
Possible mitochondrial disorder, nuclear genes v1.105 CLPB Arina Puzriakova edited their review of gene: CLPB: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the MOI update on this panel from biallelic to both based on current evidence.; Changed rating: GREEN; Changed publications to: 34140661, 34115842; Changed phenotypes to: 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835, Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.105 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23281071, 33865955, 28275242; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex III deficiency v1.8 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23281071, 33865955, 28275242; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 UQCRC1 Arina Puzriakova reviewed gene: UQCRC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 30788857, 33141179; Phenotypes: Parkinsonism with polyneuropathy, OMIM: 619279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mitochondrial disorder with complex III deficiency v1.8 UQCRC1 Arina Puzriakova reviewed gene: UQCRC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 30788857, 33141179; Phenotypes: Parkinsonism with polyneuropathy, OMIM: 619279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 PET117 Arina Puzriakova reviewed gene: PET117: Rating: AMBER; Mode of pathogenicity: ; Publications: 28386624; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 19, OMIM: 619063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 NFS1 Arina Puzriakova reviewed gene: NFS1: Rating: AMBER; Mode of pathogenicity: ; Publications: 24498631; Phenotypes: Combined oxidative phosphorylation deficiency 52, OMIM: 619386; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 TWNK Arina Puzriakova reviewed gene: TWNK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM: 609286, Perrault syndrome 5, OMIM: 616138, Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM 271245; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial DNA maintenance disorder v1.16 TWNK Arina Puzriakova reviewed gene: TWNK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM: 609286, Perrault syndrome 5, OMIM: 616138, Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM 271245; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 33471299, 10976639, 27683074; Phenotypes: Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259, Cardiomyopathy, dilated, 1GG, OMIM: 613642; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex II deficiency v1.5 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 33471299, 10976639, 27683074; Phenotypes: Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259, Cardiomyopathy, dilated, 1GG, OMIM: 613642; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 QRSL1 Arina Puzriakova reviewed gene: QRSL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29440775, 30283131, 26741492; Phenotypes: Combined oxidative phosphorylation deficiency 40, OMIM: 618835; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.105 POLG2 Arina Puzriakova reviewed gene: POLG2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31778857, 21555342, 27592148, 16685652; Phenotypes: ?Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM: 618528, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM: 610131, ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM: 619425; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial DNA maintenance disorder v1.16 POLG2 Arina Puzriakova reviewed gene: POLG2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31778857, 21555342, 27592148, 16685652; Phenotypes: ?Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM: 618528, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM: 610131, ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM: 619425; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.104 COX16 Arina Puzriakova edited their review of gene: COX16: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on current evidence.; Changed rating: AMBER; Set current diagnostic: yes
Mitochondrial disorder with complex IV deficiency v1.18 COX16 Arina Puzriakova edited their review of gene: COX16: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on current evidence.; Changed rating: AMBER; Set current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.103 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex III deficiency v1.7 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.103 TIMMDC1 Arina Puzriakova edited their review of gene: TIMMDC1: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed publications to: 33278652, 28604674
Mitochondrial disorder with complex I deficiency v1.18 TIMMDC1 Arina Puzriakova edited their review of gene: TIMMDC1: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed publications to: 33278652, 28604674
Possible mitochondrial disorder, nuclear genes v1.103 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 31785789, 32399598, 27448789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial DNA maintenance disorder v1.15 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 31785789, 32399598, 27448789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.102 POLRMT Arina Puzriakova edited their review of gene: POLRMT: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the rating upgrade from Amber to Green on this panel.; Changed rating: GREEN; Changed publications to: 33602924; Changed phenotypes to: Combined oxidative phosphorylation deficiency 55, OMIM: 619743; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.102 TARS2 Arina Puzriakova reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21, OMIM: 615918; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.102 SDHB Arina Puzriakova reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 22972948, 32124427, 26925370, 27604842; Phenotypes: Mitochondrial complex II deficiency, nuclear type 4, OMIM: 619224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex II deficiency v1.4 SDHB Arina Puzriakova reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 22972948, 32124427, 26925370, 27604842; Phenotypes: Mitochondrial complex II deficiency, nuclear type 4, OMIM: 619224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.101 NSUN3 Arina Puzriakova reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32488845, 27356879; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM: 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.100 NDUFC2 Arina Puzriakova reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32969598; Phenotypes: Mitochondrial complex I deficiency, nuclear type 36, OMIM: 619170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.17 NDUFC2 Arina Puzriakova reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32969598; Phenotypes: Mitochondrial complex I deficiency, nuclear type 36, OMIM: 619170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.99 SSBP1 Arina Puzriakova commented on gene: SSBP1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from unknown to both mono- and biallelic inline with this review. Carl Fratter mentions additional cases have been seen within NHS GMS (not published).
Mitochondrial DNA maintenance disorder v1.14 SSBP1 Arina Puzriakova commented on gene: SSBP1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from unknown to both mono- and biallelic inline with this review. Carl Fratter mentions additional cases have been seen within NHS GMS (not published).
Possible mitochondrial disorder, nuclear genes v1.99 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.17 NDUFB10 Arina Puzriakova commented on gene: NDUFB10: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder, nuclear genes v1.99 NDUFA8 Arina Puzriakova commented on gene: NDUFA8: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Mitochondrial disorder with complex I deficiency v1.17 NDUFA8 Arina Puzriakova commented on gene: NDUFA8: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder, nuclear genes v1.99 NDUFA13 Arina Puzriakova commented on gene: NDUFA13: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Mitochondrial disorder with complex I deficiency v1.17 NDUFA13 Arina Puzriakova commented on gene: NDUFA13: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder, nuclear genes v1.99 NDUFA12 Arina Puzriakova commented on gene: NDUFA12: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Mitochondrial disorder with complex I deficiency v1.17 NDUFA12 Arina Puzriakova commented on gene: NDUFA12: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder, nuclear genes v1.99 LYRM4 Arina Puzriakova commented on gene: LYRM4: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder, nuclear genes v1.99 COX6A2 Arina Puzriakova edited their review of gene: COX6A2: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 31155743, 23460811, 32744742; Changed phenotypes to: Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes
Mitochondrial disorder with complex IV deficiency v1.17 COX6A2 Arina Puzriakova edited their review of gene: COX6A2: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 31155743, 23460811, 32744742; Changed phenotypes to: Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.99 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Set current diagnostic: yes
Mitochondrial disorder with complex V deficiency v1.10 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Set current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.99 ATP5A1 Arina Puzriakova commented on gene: ATP5A1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from biallelic to both mono- and biallelic inline with this review.
Mitochondrial disorder with complex V deficiency v1.10 ATP5A1 Arina Puzriakova commented on gene: ATP5A1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from biallelic to both mono- and biallelic inline with this review.
Mitochondrial disorders v2.123 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28275242, 23281071, 33865955; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28275242, 23281071, 33865955; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 27683074, 10976639, 33471299; Phenotypes: Cardiomyopathy, dilated, 1GG, OMIM: 613642, Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 27683074, 10976639, 33471299; Phenotypes: Cardiomyopathy, dilated, 1GG, OMIM: 613642, Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.98 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.123 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 32399598, 27448789, 31785789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 32399598, 27448789, 31785789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 SDHB Arina Puzriakova reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 27604842, 32124427, 22972948, 26925370; Phenotypes: Mitochondrial complex II deficiency, nuclear type 4, OMIM: 619224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NSUN3 Arina Puzriakova reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27356879, 32488845; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM: 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 NSUN3 Arina Puzriakova reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27356879, 32488845; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM: 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NDUFC2 Arina Puzriakova reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32969598; Phenotypes: Mitochondrial complex I deficiency, nuclear type 36, OMIM: 619170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.98 SSBP1 Arina Puzriakova reviewed gene: SSBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34905022, 31550240, 31550237, 31298765, 31479473; Phenotypes: Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial DNA maintenance disorder v1.13 SSBP1 Arina Puzriakova reviewed gene: SSBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34905022, 31550240, 31550237, 31298765, 31479473; Phenotypes: Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.16 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.123 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.98 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism v2.265 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.98 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder, nuclear genes v1.98 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: ; Publications: 33715266, 21617257, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: ; Publications: 33715266, 21617257, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Undiagnosed metabolic disorders v1.552 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.98 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.123 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the rating should be upgraded from Amber to Green on Mitochondrial panels (R357 and R63). As there is sufficient supporting evidence, the rating should also be updated to Green on this panel at the next GMS review.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.265 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the rating should be upgraded from Amber to Green on Mitochondrial panels (R357 and R63). As there is sufficient supporting evidence, the rating should also be updated to Green on this panel at the next GMS review.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.265 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.98 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex V deficiency v1.9 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.582 SLC32A1 Helen Lord reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34038384, Platzer et al, 2022 - not on pubmed curently; Phenotypes: developmental and epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset dystonia v1.120 HPRT1 Eldar Dedic changed review comment from: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, the c.384+1G>A and c.384+1G>A variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.; to: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, the c.486-1G>A and c.384+1G>A variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.
Early onset dystonia v1.120 HPRT1 Eldar Dedic changed review comment from: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, all variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.; to: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, the c.384+1G>A and c.384+1G>A variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.
Early onset dystonia v1.120 HPRT1 Eldar Dedic reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16549399; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1696 DOCK8 Tracy Lester reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: 18060736, 1764478, 27891178, 19776401; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.122 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Likely inborn error of metabolism v2.264 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Possible mitochondrial disorder, nuclear genes v1.97 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Tag Q3_22_NHS_review tag was added to gene: UQCRC2.
Mitochondrial disorder with complex III deficiency v1.6 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Tag Q3_22_NHS_review tag was added to gene: UQCRC2.
Paediatric or syndromic cardiomyopathy v1.78 SDHA Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'biallelic' only to 'both mono- and biallelic' as cardiomyopathy has also been shown to be a feature associated with heterozygous variants in this gene (PMID: 27683074)
Paediatric or syndromic cardiomyopathy v1.78 SDHA Arina Puzriakova Mode of inheritance for gene: SDHA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Added comment: Comment on mode of inheritance: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the MOI should be updated from 'biallelic' only to 'both mono- and biallelic' on Mitochondrial GMS panels (R354 and R63). As there was sufficient supporting evidence for the change, the MOI has also been updated to 'both' on this panel to ensure all panels reflect correct knowledge. Heterozygous variants can be associated with abnormal mitochondrial accumulation and therefore also within the scope of the panel.
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Mode of inheritance for gene: SDHA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.97 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Tag Q3_22_NHS_review tag was added to gene: SDHA.
Mitochondrial disorder with complex II deficiency v1.3 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Tag Q3_22_NHS_review tag was added to gene: SDHA.
Likely inborn error of metabolism v2.264 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Mitochondrial disorders v2.122 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Possible mitochondrial disorder, nuclear genes v1.97 CLPB Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: CLPB.
Mitochondrial disorders v2.122 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Likely inborn error of metabolism v2.264 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Possible mitochondrial disorder, nuclear genes v1.97 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Tag Q3_22_NHS_review tag was added to gene: UQCRFS1.
Mitochondrial disorder with complex III deficiency v1.6 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Tag Q3_22_NHS_review tag was added to gene: UQCRFS1.
Mitochondrial disorders v2.122 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Likely inborn error of metabolism v2.264 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Possible mitochondrial disorder, nuclear genes v1.97 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Tag Q3_22_NHS_review tag was added to gene: TIMMDC1.
Mitochondrial disorder with complex I deficiency v1.15 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Tag Q3_22_NHS_review tag was added to gene: TIMMDC1.
Mitochondrial disorders v2.122 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Likely inborn error of metabolism v2.264 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Possible mitochondrial disorder, nuclear genes v1.97 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Tag Q3_22_NHS_review tag was added to gene: TFAM.
Mitochondrial DNA maintenance disorder v1.12 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Tag Q3_22_NHS_review tag was added to gene: TFAM.
Possible mitochondrial disorder, nuclear genes v1.97 TARS2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TARS2.
Mitochondrial disorders v2.122 SDHB Arina Puzriakova Tag Q3_22_rating tag was added to gene: SDHB.
Possible mitochondrial disorder, nuclear genes v1.97 SDHB Arina Puzriakova Tag Q3_22_rating tag was added to gene: SDHB.
Tag Q3_22_NHS_review tag was added to gene: SDHB.
Mitochondrial disorder with complex II deficiency v1.3 SDHB Arina Puzriakova Tag Q3_22_rating tag was added to gene: SDHB.
Tag Q3_22_NHS_review tag was added to gene: SDHB.
Possible mitochondrial disorder, nuclear genes v1.97 POLRMT Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: POLRMT.
Mitochondrial disorders v2.122 NSUN3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSUN3.
Likely inborn error of metabolism v2.264 NSUN3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSUN3.
Possible mitochondrial disorder, nuclear genes v1.97 NSUN3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSUN3.
Tag Q3_22_NHS_review tag was added to gene: NSUN3.
Mitochondrial disorders v2.122 NDUFC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFC2.
Undiagnosed metabolic disorders v1.550 NDUFC2 Arina Puzriakova Tag Q2_21_rating was removed from gene: NDUFC2.
Undiagnosed metabolic disorders v1.550 NDUFC2 Arina Puzriakova Classified gene: NDUFC2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.550 NDUFC2 Arina Puzriakova Gene: ndufc2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.582 FBXO28 Sarah Leigh Mode of inheritance for gene: FBXO28 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1696 FBXO28 Sarah Leigh Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy 100 (# 619777) to Developmental and epileptic encephalopathy 100, OMIM:619777; developmental and epileptic encephalopathy 100, MONDO:0030695
Early onset or syndromic epilepsy v2.581 FBXO28 Sarah Leigh Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 100, OMIM:619777; developmental and epileptic encephalopathy 100, MONDO:0030695
Early onset or syndromic epilepsy v2.580 FBXO28 Sarah Leigh Publications for gene: FBXO28 were set to 33280099
Intellectual disability v3.1695 FBXO28 Sarah Leigh edited their review of gene: FBXO28: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh edited their review of gene: FBXO28: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXO28.
Tag Q3_22_MOI tag was added to gene: FBXO28.
Intellectual disability v3.1695 FBXO28 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXO28.
Tag Q3_22_MOI tag was added to gene: FBXO28.
Intellectual disability v3.1695 FBXO28 Sarah Leigh Classified gene: FBXO28 as Amber List (moderate evidence)
Intellectual disability v3.1695 FBXO28 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 v3.1695 FBXO28 Sarah Leigh Gene: fbxo28 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Classified gene: FBXO28 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.579 FBXO28 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 v2.579 FBXO28 Sarah Leigh Gene: fbxo28 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1694 CDK9 Sarah Leigh edited their review of gene: CDK9: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants have been reported in unrelated cases with a CHARGE-like syndrome:
NM_001261:c.280C>T, p.Arg94Cys (PMID: 29302074)
NM_001261.3:c.673C>T / p.Arg225Cys (PMID: 26633546, 30237576)
NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys (PMID: 33640901).
Supportive functional studies have also been reported (PMID: 33640901).; Changed rating: GREEN
Intellectual disability v3.1694 CDK9 Sarah Leigh Tag Q3_22_rating tag was added to gene: CDK9.
Tag Q3_22_MOI tag was added to gene: CDK9.
Possible mitochondrial disorder, nuclear genes v1.97 SSBP1 Arina Puzriakova Mode of pathogenicity for gene: SSBP1 was changed from to Other
Mitochondrial DNA maintenance disorder v1.12 SSBP1 Arina Puzriakova Mode of pathogenicity for gene: SSBP1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mitochondrial DNA maintenance disorder v1.11 SSBP1 Arina Puzriakova Mode of inheritance for gene: SSBP1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1694 CDK9 Sarah Leigh Classified gene: CDK9 as Amber List (moderate evidence)
Intellectual disability v3.1694 CDK9 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 v3.1694 CDK9 Sarah Leigh Gene: cdk9 has been classified as Amber List (Moderate Evidence).
Mitochondrial DNA maintenance disorder v1.10 SSBP1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SSBP1.
Tag Q3_22_NHS_review tag was added to gene: SSBP1.
Possible mitochondrial disorder, nuclear genes v1.96 SSBP1 Arina Puzriakova Mode of inheritance for gene: SSBP1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.95 SSBP1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SSBP1.
Tag Q3_22_NHS_review tag was added to gene: SSBP1.
Intellectual disability v3.1693 CCDC32 Sarah Leigh Tag Q3_22_rating tag was added to gene: CCDC32.
Intellectual disability v3.1693 CCDC32 Sarah Leigh edited their review of gene: CCDC32: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for CCDC32-associated neurodevelopmental syndrome. At least three variants have been reported in three unrelated cases (PMIDS: 32307552 & 35451546), together with supportive functional studies.; Changed rating: GREEN
Rare multisystem ciliopathy disorders v1.163 CCDC32 Sarah Leigh reviewed gene: CCDC32: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.264 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Mitochondrial disorders v2.122 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Possible mitochondrial disorder, nuclear genes v1.95 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Tag Q3_22_NHS_review tag was added to gene: NDUFB10.
Mitochondrial disorder with complex I deficiency v1.15 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Tag Q3_22_NHS_review tag was added to gene: NDUFB10.
Intellectual disability v3.1693 CCDC32 Sarah Leigh Classified gene: CCDC32 as Amber List (moderate evidence)
Intellectual disability v3.1693 CCDC32 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 v3.1693 CCDC32 Sarah Leigh Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Rare multisystem ciliopathy disorders v1.163 CCDC32 Sarah Leigh Classified gene: CCDC32 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.163 CCDC32 Sarah Leigh Gene: ccdc32 has been classified as Green List (High Evidence).
Mitochondrial disorders v2.122 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Likely inborn error of metabolism v2.264 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Possible mitochondrial disorder, nuclear genes v1.95 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Tag Q3_22_NHS_review tag was added to gene: NDUFA8.
Mitochondrial disorder with complex I deficiency v1.15 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Tag Q3_22_NHS_review tag was added to gene: NDUFA8.
Rare multisystem ciliopathy disorders v1.162 CCDC32 Sarah Leigh Phenotypes for gene: CCDC32 were changed from Craniofacial, cardiac, laterality and neurodevelopmental anomalies to Cardiofacioneurodevelopmental syndrome, OMIM:619123; cardiofacioneurodevelopmental syndrome, MONDO:0030873
Intellectual disability v3.1692 CCDC32 Sarah Leigh Phenotypes for gene: CCDC32 were changed from global developmental delay to Cardiofacioneurodevelopmental syndrome, OMIM:619123; cardiofacioneurodevelopmental syndrome, MONDO:0030873
Intellectual disability v3.1691 CCDC32 Sarah Leigh Publications for gene: CCDC32 were set to 32307552
Rare multisystem ciliopathy disorders v1.161 CCDC32 Sarah Leigh Publications for gene: CCDC32 were set to 32307552
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: GLRA2.
Intellectual disability v3.1690 GLRA2 Sarah Leigh Tag Q3_22_rating tag was added to gene: GLRA2.
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Tag Q3_22_rating tag was added to gene: GLRA2.
Intellectual disability v3.1690 GLRA2 Sarah Leigh Classified gene: GLRA2 as Amber List (moderate evidence)
Intellectual disability v3.1690 GLRA2 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 v3.1690 GLRA2 Sarah Leigh Gene: glra2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.264 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Mitochondrial disorders v2.122 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Mitochondrial disorder with complex I deficiency v1.15 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Tag Q3_22_NHS_review tag was added to gene: NDUFA13.
Possible mitochondrial disorder, nuclear genes v1.95 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Tag Q3_22_NHS_review tag was added to gene: NDUFA13.
Intellectual disability v3.1689 GLRA2 Sarah Leigh edited their review of gene: GLRA2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35294868 reports eight GLRA2 variants in affected females (n=8) and males (n=5). The variants in the females were de novo and c.887C>T,
p.Thr296Met (NC_000023.10, chrX: g.14627284C>T) was present in six individuals (PMID: 35294868, table 2) and was found to have a gain-of-function effect, which is in contrast to c.754C>T, p.Arg252Cys and c.407A>G, p.Asn136Ser (PMID: 2637014). All of the 13 GLRA2 variant carriers in PMID: 35294868 had developmental delay/intellectual disability and epilepsy was evident in 7/13 of the cases (PMID: 35294868, table 2). Supportive functional studies were also presented.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh edited their review of gene: GLRA2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35294868 reports eight GLRA2 variants in affected females (n=8) and males (n=5). The variants in the females were de novo and c.887C>T,
p.Thr296Met (NC_000023.10, chrX: g.14627284C>T) was present in six individuals (PMID: 35294868, table 2) and was found to have a gain-of-function effect, which is in contrast to c.754C>T, p.Arg252Cys and c.407A>G, p.Asn136Ser (PMID: 2637014). All of the 13 GLRA2 variant carriers in PMID: 35294868 had developmental delay/intellectual disability and epilepsy was evident in 7/13 of the cases (PMID: 35294868, table 2). Supportive functional studies were also presented.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Classified gene: GLRA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.578 GLRA2 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 v2.578 GLRA2 Sarah Leigh Gene: glra2 has been classified as Amber List (Moderate Evidence).
Early onset dystonia v1.120 NDUFA12 Arina Puzriakova Classified gene: NDUFA12 as Green List (high evidence)
Early onset dystonia v1.120 NDUFA12 Arina Puzriakova Added comment: Comment on list classification: Gene was recently upgraded to Green on GMS panels and therefore also updating the rating here to ensure all panels display correct knowledge.
Early onset dystonia v1.120 NDUFA12 Arina Puzriakova Gene: ndufa12 has been classified as Green List (High Evidence).
Early onset dystonia v1.119 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.119 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency 256000 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Undiagnosed metabolic disorders v1.549 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Early onset dystonia v1.118 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Undiagnosed metabolic disorders v1.548 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 27604308
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Classified gene: NDUFA12 as Green List (high evidence)
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Added comment: Comment on list classification: Gene was recently upgraded from Amber to Green on GMS panels and therefore also updating the rating here to ensure all panels display correct knowledge.
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Gene: ndufa12 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.546 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v2.73 NDUFA12 Arina Puzriakova Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.251
Optic neuropathy v2.73 NDUFA12 Arina Puzriakova gene: NDUFA12 was added
gene: NDUFA12 was added to Optic neuropathy. Sources: Expert Review Amber,PanelApp,South West GLH
Q3_22_rating tags were added to gene: NDUFA12.
Mode of inheritance for gene: NDUFA12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA12 were set to 21617257; 33715266; 35141356
Phenotypes for gene: NDUFA12 were set to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Hereditary spastic paraplegia, childhood onset v2.146 NDUFA12 Arina Puzriakova Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.251
Hereditary spastic paraplegia, childhood onset v2.146 NDUFA12 Arina Puzriakova gene: NDUFA12 was added
gene: NDUFA12 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,PanelApp,South West GLH
Q3_22_rating tags were added to gene: NDUFA12.
Mode of inheritance for gene: NDUFA12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA12 were set to 21617257; 33715266; 35141356
Phenotypes for gene: NDUFA12 were set to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Dystonia, chorea or related movement disorder, childhood onset v1.251 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency 256000; ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Dystonia, chorea or related movement disorder, childhood onset v1.250 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Dystonia, chorea or related movement disorder, childhood onset v1.249 NDUFA12 Arina Puzriakova Classified gene: NDUFA12 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.249 NDUFA12 Arina Puzriakova Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.248 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.248 NDUFA12 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA12.
Possible mitochondrial disorder, nuclear genes v1.95 NDUFA12 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA12.
Tag Q3_22_NHS_review tag was added to gene: NDUFA12.
Mitochondrial disorder with complex I deficiency v1.15 NDUFA12 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA12.
Tag Q3_22_NHS_review tag was added to gene: NDUFA12.
Intellectual disability v3.1689 GLRA2 Sarah Leigh Phenotypes for gene: GLRA2 were changed from Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076; intellectual developmental disorder, X-linked, syndromic, Pilorge type, MONDO:0024772 to Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076; intellectual developmental disorder, X-linked, syndromic, Pilorge type, MONDO:0024772
Intellectual disability v3.1689 GLRA2 Sarah Leigh Phenotypes for gene: GLRA2 were changed from autism spectrum disorder to Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076; intellectual developmental disorder, X-linked, syndromic, Pilorge type, MONDO:0024772
Intellectual disability v3.1688 GLRA2 Sarah Leigh Publications for gene: GLRA2 were set to 28588452; 26370147; 29057625
Intellectual disability v3.1687 NRCAM Sarah Leigh edited their review of gene: NRCAM: Added comment: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for NRCAM neurodevelopmental disorder with dysmorphic features, hypotonia and spasticity. At least 12 variants have been reported in PMID: 35108495 in 8 unrelated cases (table 1). Global developmental delay / intellectual disabilty was evident in 5/7 unrelated cases (individual 1 was not considered as they also had homozygous loss-of-function variant in CD55 (OMIM: 125240)(PMID: 35108495).; Changed rating: GREEN
Intellectual disability v3.1687 NRCAM Sarah Leigh Tag Q3_22_rating tag was added to gene: NRCAM.
Tag Q3_22_MOI tag was added to gene: NRCAM.
Intellectual disability v3.1687 NRCAM Sarah Leigh Classified gene: NRCAM as Amber List (moderate evidence)
Intellectual disability v3.1687 NRCAM 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 v3.1687 NRCAM Sarah Leigh Gene: nrcam has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1686 NRCAM Sarah Leigh Phenotypes for gene: NRCAM were changed from Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Primary immunodeficiency or monogenic inflammatory bowel disease v2.573 FOXI3 Boaz Palterer gene: FOXI3 was added
gene: FOXI3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 35987349
Phenotypes for gene: FOXI3 were set to T-cell lymphopenia; low TREC; thymic hypoplasia
Penetrance for gene: FOXI3 were set to Incomplete
Review for gene: FOXI3 was set to AMBER
Added comment: Ghosh et al. described 2 unrelated patients with T cell lymphopenia, positive TREC screening and thymic hypoplasia with deleterious FOXI3 variants. FOXI3 was demonstrated in mice models to be involved in thymic development.
Sources: Literature
Rare anaemia v1.42 HEATR3 Sarah Leigh Tag Q3_22_rating tag was added to gene: HEATR3.
Tag Q3_22_MOI tag was added to gene: HEATR3.
Likely inborn error of metabolism v2.264 LYRM4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: LYRM4.
Mitochondrial disorders v2.122 LYRM4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: LYRM4.
Possible mitochondrial disorder, nuclear genes v1.95 LYRM4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: LYRM4.
Tag Q3_22_NHS_review tag was added to gene: LYRM4.
Congenital myopathy v2.90 COX6A2 Arina Puzriakova Entity copied from Mitochondrial disorders v2.122
Congenital myopathy v2.90 COX6A2 Arina Puzriakova gene: COX6A2 was added
gene: COX6A2 was added to Congenital myopathy. Sources: Expert Review Amber,NHS GMS
Q3_22_rating tags were added to gene: COX6A2.
Mode of inheritance for gene: COX6A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX6A2 were set to 23460811; 31155743; 32744742
Phenotypes for gene: COX6A2 were set to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Mitochondrial disorder with complex IV deficiency v1.16 COX6A2 Arina Puzriakova commented on gene: COX6A2
Possible mitochondrial disorder, nuclear genes v1.95 COX6A2 Arina Puzriakova commented on gene: COX6A2
Mitochondrial disorders v2.122 COX6A2 Arina Puzriakova Classified gene: COX6A2 as Amber List (moderate evidence)
Mitochondrial disorders v2.122 COX6A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least two unrelated cases harbouring different biallelic variants in this gene (PMID: 31155743) and presenting with a consistent phenotype of congenital myopathy. Functional studies and two mouse models are supportive of pathogenicity (PMID: 23460811; 31155743; 32744742)
Mitochondrial disorders v2.122 COX6A2 Arina Puzriakova Gene: cox6a2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.121 COX6A2 Arina Puzriakova Mode of inheritance for gene: COX6A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.120 COX6A2 Arina Puzriakova Publications for gene: COX6A2 were set to
Mitochondrial disorders v2.119 COX6A2 Arina Puzriakova Phenotypes for gene: COX6A2 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Possible mitochondrial disorder, nuclear genes v1.95 COX6A2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: COX6A2.
Tag Q3_22_NHS_review tag was added to gene: COX6A2.
Mitochondrial disorder with complex IV deficiency v1.16 COX6A2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: COX6A2.
Tag Q3_22_NHS_review tag was added to gene: COX6A2.
Mitochondrial disorders v2.118 COX6A2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: COX6A2.
Rare anaemia v1.42 HEATR3 Sarah Leigh edited their review of gene: HEATR3: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; Changed rating: GREEN
Rare anaemia v1.42 HEATR3 Sarah Leigh Deleted their comment
Rare anaemia v1.42 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.
Rare anaemia v1.42 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.
Rare anaemia v1.42 HEATR3 Sarah Leigh Entity copied from Intellectual disability v3.1685
Rare anaemia v1.42 HEATR3 Sarah Leigh gene: HEATR3 was added
gene: HEATR3 was added to Rare anaemia. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
Intellectual disability v3.1685 HEATR3 Sarah Leigh reviewed gene: HEATR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1685 HEATR3 Sarah Leigh Classified gene: HEATR3 as Amber List (moderate evidence)
Intellectual disability v3.1685 HEATR3 Sarah Leigh Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.264 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Mitochondrial disorders v2.118 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Mitochondrial disorder with complex V deficiency v1.8 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Tag Q3_22_NHS_review tag was added to gene: ATP5G3.
Possible mitochondrial disorder, nuclear genes v1.95 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Tag Q3_22_NHS_review tag was added to gene: ATP5G3.
Likely inborn error of metabolism v2.264 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Mitochondrial disorders v2.118 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Mitochondrial disorder with complex V deficiency v1.8 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Possible mitochondrial disorder, nuclear genes v1.95 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Dystonia, chorea or related movement disorder, childhood onset v1.248 ATP5G3 Arina Puzriakova Classified gene: ATP5G3 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.248 ATP5G3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene as Green at the next GMS panel update - at least four unrelated families with heterozygous variants primarily presenting with dystonia or related movement disorder (PMID: 34636445; 34954817); also supportive Drosophila model described.
Dystonia, chorea or related movement disorder, childhood onset v1.248 ATP5G3 Arina Puzriakova Gene: atp5g3 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.247 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from Dystonia, early-onset, and/or spastic paraplegia, MIM# 619681 to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Dystonia, chorea or related movement disorder, childhood onset v1.246 ATP5G3 Arina Puzriakova Tag new-gene-name tag was added to gene: ATP5G3.
Tag Q3_22_rating tag was added to gene: ATP5G3.
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh edited their review of gene: TIAM1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35240055 reports six TIAM1 variants in four unrelated cases (5 cases in total) of Neurodevelopmental disorder with language delay and seizures, OMIM:619908. All of the cases displayed seizures and intellectual disability, where an assessment was made. The drospohila ortholog (still life) and funtional studies supported this gene disease association (PMID: 35240055).; Changed rating: GREEN
Intellectual disability v3.1684 TIAM1 Sarah Leigh edited their review of gene: TIAM1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35240055 reports six TIAM1 variants in four unrelated cases (5 cases in total) of Neurodevelopmental disorder with language delay and seizures, OMIM:619908. All of the cases displayed seizures and intellectual disability, where an assessment was made. The drospohila ortholog (still life) and funtional studies supported this gene disease association (PMID: 35240055).; Changed rating: GREEN
Intellectual disability v3.1684 TIAM1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TIAM1.
Tag Q3_22_MOI tag was added to gene: TIAM1.
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TIAM1.
Tag Q3_22_MOI tag was added to gene: TIAM1.
Intellectual disability v3.1684 TIAM1 Sarah Leigh Phenotypes for gene: TIAM1 were changed from Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology to Neurodevelopmental disorder with language delay and seizures, OMIM:619908
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh Phenotypes for gene: TIAM1 were changed from Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology to Neurodevelopmental disorder with language delay and seizures, OMIM:619908
Intellectual disability v3.1683 TIAM1 Sarah Leigh Classified gene: TIAM1 as Amber List (moderate evidence)
Intellectual disability v3.1683 TIAM1 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 v3.1683 TIAM1 Sarah Leigh Gene: tiam1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Classified gene: TIAM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.576 TIAM1 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 v2.576 TIAM1 Sarah Leigh Gene: tiam1 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.546 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); ?Combined oxidative phosphorylation deficiency 22 616045; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228 to Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Classified gene: ATP5A1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to support this gene-disease association and therefore ATP5A1 has been promoted to Green.
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Gene: atp5a1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.544 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 27604308; 23599390; 23596069
Undiagnosed metabolic disorders v1.543 ATP5A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Two families (with two affected sibs each) reported with recessive variants and supported by functional studies (PMIDs: 23599390; 23596069). Six unrelated patients have been reported with heterozygous variants; including one recurrent variant c.620G>A in four cases, c.545G>A and c.1037C>T in the remaining two, respectively (PMIDs: 34483339; 34954817).
Undiagnosed metabolic disorders v1.543 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.264 ATP5A1 Arina Puzriakova Tag Q3_22_MOI was removed from gene: ATP5A1.
Tag Q3_22_rating tag was added to gene: ATP5A1.
Likely inborn error of metabolism v2.264 ATP5A1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: ATP5A1.
Likely inborn error of metabolism v2.264 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.118 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.117 ATP5A1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5A1.
Possible mitochondrial disorder, nuclear genes v1.95 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.94 ATP5A1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5A1.
Tag Q3_22_NHS_review tag was added to gene: ATP5A1.
Mitochondrial disorder with complex V deficiency v1.8 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex V deficiency v1.7 ATP5A1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5A1.
Tag Q3_22_NHS_review tag was added to gene: ATP5A1.
Severe microcephaly v2.317 CPSF3 Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.575
Severe microcephaly v2.317 CPSF3 Sarah Leigh gene: CPSF3 was added
gene: CPSF3 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Penetrance for gene: CPSF3 were set to Complete
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh reviewed gene: CPSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh Classified gene: CPSF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh Gene: cpsf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1682 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, (NM_016207.3) in two Icelandic families and c.1061T>C (NM_016207.3) in a large consanguineous Mexican family.; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
Intellectual disability v3.1682 CPSF3 Sarah Leigh reviewed gene: CPSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1682 CPSF3 Sarah Leigh Classified gene: CPSF3 as Amber List (moderate evidence)
Intellectual disability v3.1682 CPSF3 Sarah Leigh Gene: cpsf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1681 CPSF3 Sarah Leigh Phenotypes for gene: CPSF3 were changed from Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Early onset or syndromic epilepsy v2.574 CPSF3 Sarah Leigh Phenotypes for gene: CPSF3 were changed from Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Intellectual disability v3.1680 PDZD8 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.; to: Not associated with a phenotype in OMIM (last edited: 02/21/2018), Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.
Intellectual disability v3.1680 PDZD8 Sarah Leigh Tag Q3_22_rating tag was added to gene: PDZD8.
Tag Q3_22_MOI tag was added to gene: PDZD8.
Intellectual disability v3.1680 PDZD8 Sarah Leigh edited their review of gene: PDZD8: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.; Changed rating: GREEN
Intellectual disability v3.1680 PDZD8 Sarah Leigh Classified gene: PDZD8 as Amber List (moderate evidence)
Intellectual disability v3.1680 PDZD8 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 v3.1680 PDZD8 Sarah Leigh Gene: pdzd8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1679 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Severe microcephaly v2.316 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Severe microcephaly v2.316 CHKA Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.573
Severe microcephaly v2.316 CHKA Sarah Leigh gene: CHKA was added
gene: CHKA was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Intellectual disability v3.1679 CHKA Sarah Leigh edited their review of gene: CHKA: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh edited their review of gene: CHKA: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.; Changed rating: GREEN
Intellectual disability v3.1679 CHKA Sarah Leigh Classified gene: CHKA as Amber List (moderate evidence)
Intellectual disability v3.1679 CHKA 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 v3.1679 CHKA Sarah Leigh Gene: chka has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Classified gene: CHKA as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.573 CHKA 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 v2.573 CHKA Sarah Leigh Gene: chka has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.248 KDM3B Sarah Leigh Phenotypes for gene: KDM3B were changed from Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures to Diets-Jongmans syndrome, OMIM:618846; Diets-Jongmans syndrome, MONDO:0030012
DDG2P v2.79 KDM3B Sarah Leigh Phenotypes for gene: KDM3B were changed from Intellectual Disability, Short Stature, and Facial Dysmorphism; KDM3B-related intellectual disability, short stature and facial dysmorphism to Diets-Jongmans syndrome, OMIM:618846; Diets-Jongmans syndrome, MONDO:0030012
Intellectual disability v3.1678 KDM3B Sarah Leigh Phenotypes for gene: KDM3B were changed from Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures to Diets-Jongmans syndrome, OMIM:618846; Diets-Jongmans syndrome, MONDO:0030012
Hereditary ataxia v1.304 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641; 11555633; 33159930
Ataxia and cerebellar anomalies - childhood onset v2.302 PRDM13 Arina Puzriakova Classified gene: PRDM13 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.302 PRDM13 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Ataxia and cerebellar anomalies - childhood onset v2.302 PRDM13 Arina Puzriakova Gene: prdm13 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.301 PRDM13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: PRDM13.
Ataxia and cerebellar anomalies - childhood onset v2.301 PRDM13 Arina Puzriakova Entity copied from Cerebellar hypoplasia v1.64
Ataxia and cerebellar anomalies - childhood onset v2.301 PRDM13 Arina Puzriakova gene: PRDM13 was added
gene: PRDM13 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Green,Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 35390279; 34730112
Phenotypes for gene: PRDM13 were set to Pontocerebellar hypoplasia, type 17, OMIM:619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Cerebellar hypoplasia v1.64 PRDM13 Arina Puzriakova Phenotypes for gene: PRDM13 were changed from Cerebellar hypoplasia to Pontocerebellar hypoplasia, type 17, OMIM:619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Neurodegenerative disorders, adult onset v2.277 XK Arina Puzriakova Tag Q3_22_rating tag was added to gene: XK.
Neurodegenerative disorders, adult onset v2.277 XK Arina Puzriakova Classified gene: XK as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.277 XK Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next major review. Neurodegenerative component resembling Huntington disease becomes apparent in older individuals.
Neurodegenerative disorders, adult onset v2.277 XK Arina Puzriakova Gene: xk has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.276 XK Arina Puzriakova Entity copied from Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.79
Neurodegenerative disorders, adult onset v2.276 XK Arina Puzriakova gene: XK was added
gene: XK was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: XK 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: XK were set to 30128557; 20301528; 8004674
Phenotypes for gene: XK were set to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Penetrance for gene: XK were set to Complete
Fetal anomalies v1.963 UNC13D Arina Puzriakova Publications for gene: UNC13D were set to PMID: 33249554
Fetal anomalies v1.962 UNC13D Arina Puzriakova Classified gene: UNC13D as Amber List (moderate evidence)
Fetal anomalies v1.962 UNC13D Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.962 UNC13D Arina Puzriakova Gene: unc13d has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.961 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from MITOCHONDRIAL DNA DEPLETION SYNDROME, MYOPATHIC FORM to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Fetal anomalies v1.960 TK2 Arina Puzriakova Classified gene: TK2 as Amber List (moderate evidence)
Fetal anomalies v1.960 TK2 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.960 TK2 Arina Puzriakova Gene: tk2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.959 TK2 Arina Puzriakova Tag watchlist tag was added to gene: TK2.
Fetal anomalies v1.959 THSD1 Arina Puzriakova Classified gene: THSD1 as Amber List (moderate evidence)
Fetal anomalies v1.959 THSD1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.959 THSD1 Arina Puzriakova Gene: thsd1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.958 THSD1 Arina Puzriakova Publications for gene: THSD1 were set to PMID: 28749478; 26036949
Fetal anomalies v1.957 ST3GAL5 Arina Puzriakova Phenotypes for gene: ST3GAL5 were changed from AMISH INFANTILE EPILEPSY SYNDROME to Infantile epilepsy
Fetal anomalies v1.956 ST3GAL5 Arina Puzriakova Publications for gene: ST3GAL5 were set to
Fetal anomalies v1.955 SERPINA11 Arina Puzriakova Publications for gene: SERPINA11 were set to PMID: 31742715; 28749478
Fetal anomalies v1.954 SERPINA11 Arina Puzriakova Classified gene: SERPINA11 as Amber List (moderate evidence)
Fetal anomalies v1.954 SERPINA11 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.954 SERPINA11 Arina Puzriakova Gene: serpina11 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.953 PIGS Arina Puzriakova Publications for gene: PIGS were set to PMID: 30269814
Fetal anomalies v1.952 PIGS Arina Puzriakova Phenotypes for gene: PIGS were changed from Developmental and epileptic encephalopathy 95 to Developmental and epileptic encephalopathy 95, OMIM:618143
Fetal anomalies v1.951 PIGS Arina Puzriakova Classified gene: PIGS as Amber List (moderate evidence)
Fetal anomalies v1.951 PIGS Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.951 PIGS Arina Puzriakova Gene: pigs has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.950 NUP88 Arina Puzriakova Publications for gene: NUP88 were set to 30543681
Fetal anomalies v1.949 NONO Arina Puzriakova Tag watchlist tag was added to gene: NONO.
Fetal anomalies v1.949 NONO Arina Puzriakova Publications for gene: NONO were set to 32397791
Fetal anomalies v1.948 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from Mitochondrial complex I deficiency to Mitochondrial complex I deficiency, nuclear type 35 , OMIM:619003
Fetal anomalies v1.947 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to PMID: 31130284; 28040730
Fetal anomalies v1.946 NDUFB10 Arina Puzriakova Classified gene: NDUFB10 as Amber List (moderate evidence)
Fetal anomalies v1.946 NDUFB10 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.946 NDUFB10 Arina Puzriakova Gene: ndufb10 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.945 MYBPC3 Arina Puzriakova Classified gene: MYBPC3 as Amber List (moderate evidence)
Fetal anomalies v1.945 MYBPC3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.

Note that the two fetal cases reported in literature harboured homozygous variants (PMID:19858127; 28749478) although expert reviewer suggests an MOI of 'both mono- and biallelic'
Fetal anomalies v1.945 MYBPC3 Arina Puzriakova Gene: mybpc3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.944 MYBPC3 Arina Puzriakova Publications for gene: MYBPC3 were set to PMID: 28749478; 19858127
Fetal anomalies v1.943 MRPS16 Arina Puzriakova Publications for gene: MRPS16 were set to PMID: 28749478
Fetal anomalies v1.942 MRPS16 Arina Puzriakova Classified gene: MRPS16 as Amber List (moderate evidence)
Fetal anomalies v1.942 MRPS16 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.942 MRPS16 Arina Puzriakova Gene: mrps16 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.941 MANBA Arina Puzriakova Publications for gene: MANBA were set to
Fetal anomalies v1.940 LOX Arina Puzriakova Publications for gene: LOX were set to PMID: 31742715
Fetal anomalies v1.939 LOX Arina Puzriakova Classified gene: LOX as Amber List (moderate evidence)
Fetal anomalies v1.939 LOX Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.939 LOX Arina Puzriakova Gene: lox has been classified as Amber List (Moderate Evidence).
Stickler syndrome v2.27 BMP4 martin snead reviewed gene: BMP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979589, 30568244, 35022715, 34926457; Phenotypes: AD Stickler syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Stickler syndrome v2.27 VCAN martin snead reviewed gene: VCAN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12208278, 10729292, 11812423; Phenotypes: Ocular-only Stickler syndrome, Wagner syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Stickler syndrome v2.27 VCAN martin snead Deleted their review
Stickler syndrome v2.27 VCAN martin snead gene: VCAN was added
gene: VCAN was added to Stickler syndrome. Sources: Expert Review
Mode of inheritance for gene: VCAN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCAN were set to Snead M, Richards A. A frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration. Am J Ophthalmol. 2002 Sep; 134(3):473; author reply 473-4. doi: 10.1016/s0002-9394(02)01635-5. PMID: 12208278.
Phenotypes for gene: VCAN were set to Ocular-only Stickler syndrome; Wagner syndrome
Penetrance for gene: VCAN were set to Complete
Review for gene: VCAN was set to GREEN
Added comment: VCAN needs to be added to the Stickler panel because Ocular-only Stickler syndrome is frequently mis-diagnosed as Wagner syndrome and vice versa. Although the 2 conditions are distinguishable by vitreous phenotyping, this may not be feasible in children or any patient who has undergone previous vitrectomy surgery.
Sources: Expert Review
Fetal anomalies v1.938 FTO Arina Puzriakova Publications for gene: FTO were set to PMID: 31130284; 19559399; 26378117
Fetal anomalies v1.937 FTO Arina Puzriakova Classified gene: FTO as Amber List (moderate evidence)
Fetal anomalies v1.937 FTO Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.937 FTO Arina Puzriakova Gene: fto has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.936 FOXP2 Arina Puzriakova Phenotypes for gene: FOXP2 were changed from SPEECH-LANGUAGE DISORDER 1 to Speech-language disorder-1, OMIM:602081; Structural abnormalities of basal ganglia
Fetal anomalies v1.935 FOXP2 Arina Puzriakova Publications for gene: FOXP2 were set to
Fetal anomalies v1.934 ENG Arina Puzriakova Phenotypes for gene: ENG were changed from Telangiectasia, hereditary hemorrhagic, type 1 to Telangiectasia, hereditary hemorrhagic, type 1, OMIM:187300
Fetal anomalies v1.933 ENG Arina Puzriakova Classified gene: ENG as Amber List (moderate evidence)
Fetal anomalies v1.933 ENG Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.933 ENG Arina Puzriakova Gene: eng has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.932 EDA Arina Puzriakova Classified gene: EDA as Green List (high evidence)
Fetal anomalies v1.932 EDA Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update in line with the recent Red review by Rhiannon Mellis (GOSH).
Fetal anomalies v1.932 EDA Arina Puzriakova Gene: eda has been classified as Green List (High Evidence).
Fetal anomalies v1.931 EDA Arina Puzriakova Phenotypes for gene: EDA were changed from TOOTH AGENESIS SELECTIVE X-LINKED TYPE 1; ECTODERMAL DYSPLASIA TYPE 1 to Ectodermal dysplasia 1, hypohidrotic, X-linked, OMIM:305100
Fetal anomalies v1.930 EDA Arina Puzriakova Tag Q3_22_rating tag was added to gene: EDA.
Tag Q3_22_NHS_review tag was added to gene: EDA.
Fetal anomalies v1.930 DEPDC5 Arina Puzriakova Classified gene: DEPDC5 as Amber List (moderate evidence)
Fetal anomalies v1.930 DEPDC5 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.930 DEPDC5 Arina Puzriakova Gene: depdc5 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.929 DEPDC5 Arina Puzriakova Publications for gene: DEPDC5 were set to
Fetal anomalies v1.928 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from FAMILIAL FOCAL EPILEPSY WITH VARIABLE FOCI to Epilepsy; Structural brain malformations
Fetal anomalies v1.927 DEPDC5 Arina Puzriakova Mode of inheritance for gene: DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v1.40 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v1.40 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene can now be promoted to Green status at the next GMS review.
Unexplained young onset end-stage renal disease v1.40 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v1.39 CHRM3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: CHRM3.
Unexplained kidney failure in young people v1.116 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Green List (high evidence)
Unexplained kidney failure in young people v1.116 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene has now been promoted to Green status.
Unexplained kidney failure in young people v1.116 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Green List (High Evidence).
CAKUT v1.172 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Green List (high evidence)
CAKUT v1.172 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene has now been promoted to Green status.
CAKUT v1.172 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.115 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune Belly-Like Syndrome; Low pressure congenital megabladder to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
Unexplained young onset end-stage renal disease v1.39 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Low pressure congenital megabladder; Prune Belly-Like Syndrome to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
Unexplained kidney failure in young people v1.114 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altm ller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, N rnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
Unexplained young onset end-stage renal disease v1.38 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altm ller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, N rnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
CAKUT v1.171 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altmüller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, Nürnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
Fetal anomalies v1.926 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to 22077972; 31441039; 10944224
CAKUT v1.170 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune Belly-Like Syndrome; Low pressure congenital megabladder to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
Fetal anomalies v1.925 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Amber List (moderate evidence)
Fetal anomalies v1.925 CHRM3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.925 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.924 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune belly syndrome; Megacystis to Prune belly syndrome, OMIM:100100; Megacystis
Fetal anomalies v1.923 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to PMID: 22077972; 31441039; 10944224
Fetal anomalies v1.922 CACNA1S Arina Puzriakova Publications for gene: CACNA1S were set to PMID: 33060286; 28012042
Fetal anomalies v1.921 CACNA1S Arina Puzriakova Classified gene: CACNA1S as Amber List (moderate evidence)
Fetal anomalies v1.921 CACNA1S Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.921 CACNA1S Arina Puzriakova Gene: cacna1s has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.920 CACNA1D Arina Puzriakova Mode of pathogenicity for gene: CACNA1D was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v1.919 CACNA1D Arina Puzriakova Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.918 CACNA1D Arina Puzriakova Publications for gene: CACNA1D were set to
Fetal anomalies v1.917 CACNA1D Arina Puzriakova Phenotypes for gene: CACNA1D were changed from PRIMARY ALDOSTERONISM, SEIZURES, AND NEUROLOGIC ABNORMALITIES; SINOATRIAL NODE DYSFUNCTION AND DEAFNESS to Primary aldosteronism, seizures, and neurologic abnormalities, OMIM:615474
Fetal anomalies v1.916 C1QBP Arina Puzriakova Phenotypes for gene: C1QBP were changed from Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies to Combined oxidative phosphorylation deficiency 33, OMIM:617713; Cardiomyopathy; Myopathy; Metabolic acidosis; Ologohydramnios
Fetal anomalies v1.915 C1QBP Arina Puzriakova Publications for gene: C1QBP were set to
Fetal anomalies v1.914 ASXL3 Arina Puzriakova Phenotypes for gene: ASXL3 were changed from BAINBRIDGE-ROPERS SYNDROME to Bainbridge-Ropers syndrome, OMIM:615485; Arthrogryposis
Fetal anomalies v1.913 ASXL3 Arina Puzriakova Publications for gene: ASXL3 were set to
Fetal anomalies v1.912 ASPH Arina Puzriakova Publications for gene: ASPH were set to
Fetal anomalies v1.911 AGT Arina Puzriakova Classified gene: AGT as Amber List (moderate evidence)
Fetal anomalies v1.911 AGT Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.911 AGT Arina Puzriakova Gene: agt has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.910 AGT Arina Puzriakova Publications for gene: AGT were set to PMID: 28976722
Fetal anomalies v1.909 AGT Arina Puzriakova Phenotypes for gene: AGT were changed from Renal dysgenesis to Renal tubular dysgenesis, OMIM:267430
Fetal anomalies v1.908 ACVRL1 Arina Puzriakova Publications for gene: ACVRL1 were set to
Fetal anomalies v1.907 ACVRL1 Arina Puzriakova Phenotypes for gene: ACVRL1 were changed from Telangiectasia, hereditary hemorrhagic, type 2 600376 to Telangiectasia, hereditary hemorrhagic, type 2, OMIM:600376
Fetal anomalies v1.906 ACVRL1 Arina Puzriakova Classified gene: ACVRL1 as Amber List (moderate evidence)
Fetal anomalies v1.906 ACVRL1 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.906 ACVRL1 Arina Puzriakova Gene: acvrl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1677 TAF4 Konstantinos Varvagiannis reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904126; Phenotypes: Delayed speech and language development, Intellectual disability, Behavioral abnormality, Joint laxity, Abnormality of the vertebral column, Abnormality of nervous system morphology, Abnormality of head or neck; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1677 ZMYND8 Konstantinos Varvagiannis gene: ZMYND8 was added
gene: ZMYND8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND8 were set to unknown
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Intellectual disability v3.1677 ZMYND15 Konstantinos Varvagiannis Deleted their review
Intellectual disability v3.1677 ZMYND15 Konstantinos Varvagiannis gene: ZMYND15 was added
gene: ZMYND15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND15 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND15 were set to 35916866; 32530565
Phenotypes for gene: ZMYND15 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND15 were set to unknown
Review for gene: ZMYND15 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Fetal anomalies v1.905 WNT7B Arina Puzriakova Classified gene: WNT7B as Amber List (moderate evidence)
Fetal anomalies v1.905 WNT7B Arina Puzriakova Added comment: Comment on list classification: New gene added by Julia Baptista. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Three families reported with fetuses with multiple congenital anomalies (PMID: 35790350). Biallelic variants were identified in probands of two families and parents in third family were both heterozygous for a variant found in one of the other families. Although the fetus was not available for testing, the genotype can be inferred as homozygous for the variant given the consistent phenotype between cases. Supportive zebrafish model supports pathogenicity.
Fetal anomalies v1.905 WNT7B Arina Puzriakova Gene: wnt7b has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.31 MYZAP Ivone Leong Phenotypes for gene: MYZAP were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Dilated and arrhythmogenic cardiomyopathy v1.30 MYZAP Ivone Leong Added comment: Comment on mode of pathogenicity: Changed from "Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments" to "Other". LOF does cause phenotype.
Dilated and arrhythmogenic cardiomyopathy v1.30 MYZAP Ivone Leong Mode of pathogenicity for gene: MYZAP was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Fetal anomalies v1.904 WNT7B Arina Puzriakova Tag Q3_22_rating tag was added to gene: WNT7B.
Tag Q3_22_NHS_review tag was added to gene: WNT7B.
Dilated and arrhythmogenic cardiomyopathy v1.29 MYZAP Ivone Leong Publications for gene: MYZAP were set to 34899865; doi:10.1101/mcs.a006221
Haematological malignancies cancer susceptibility v2.34 RAD21 Dmitrijs Rots gene: RAD21 was added
gene: RAD21 was added to Haematological malignancies cancer susceptibility. Sources: Literature
Mode of inheritance for gene: RAD21 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAD21 were set to 35563565
Phenotypes for gene: RAD21 were set to Children to Lymphoblastic Leukemia or Lymphoma
Penetrance for gene: RAD21 were set to Incomplete
Mode of pathogenicity for gene: RAD21 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: RAD21 was set to GREEN
Added comment: >3 cases reported with recurrent RAD21 missense variant with lymphocytic malignancy (ALL or LBL) without CdLS features + functional evidence in 35563565. Sufficient for green rating.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v1.28 RRAGD Eleanor Williams Tag Q3_22_NHS_review was removed from gene: RRAGD.
Paediatric or syndromic cardiomyopathy v1.77 RRAGD Eleanor Williams Tag Q3_22_NHS_review was removed from gene: RRAGD.
Paediatric or syndromic cardiomyopathy v1.77 RRAGD Eleanor Williams commented on gene: RRAGD: Copied this gene from the Renal tubulopathies panel. In 6 cases reported in PMID: 34607910 (Schlingmann et al 2021) the probands also had dilated cardiomyopathy. The 6 patients with Dilated cardiomyopathy were diagnosed with the condition at ages between 6 months and 14 years old.
Paediatric or syndromic cardiomyopathy v1.77 RRAGD Eleanor Williams Entity copied from Renal tubulopathies v2.62
Paediatric or syndromic cardiomyopathy v1.77 RRAGD Eleanor Williams gene: RRAGD was added
gene: RRAGD was added to Cardiomyopathies - including childhood onset. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_NHS_review tags were added to gene: RRAGD.
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to hypomagnesaemia; cardiomyopathy; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130
Penetrance for gene: RRAGD were set to Complete
Mode of pathogenicity for gene: RRAGD was set to Other
Dilated and arrhythmogenic cardiomyopathy v1.28 RRAGD Eleanor Williams Deleted their comment
Dilated and arrhythmogenic cardiomyopathy v1.28 RRAGD Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype.

As reviewer states PMID: 34607910 (Schlingmann et al 2021) reports 8 cases where patients with hypomagnesaemia were found to have heterozygous (mostly de novo) missense variants in RRAGD. 6 patients also had dilated cardiomyopathy. In addition they report a family with a heterozygous variant in RRAGD that segregated with a kidney phenotype in eight members. Abstract only accessed.; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

As reviewer states PMID: 34607910 (Schlingmann et al 2021) reports 8 cases where patients with hypomagnesaemia were found to have heterozygous (mostly de novo) missense variants in RRAGD. 6 patients also had dilated cardiomyopathy. In addition they report a family with a heterozygous variant in RRAGD that segregated with a kidney phenotype in eight members.
Dilated and arrhythmogenic cardiomyopathy v1.28 RRAGD Eleanor Williams changed review comment from: Copied this gene from the Renal tubulopathies panel. In 6 cases reported in PMID: 34607910 (Schlingmann et al 2021) the probands also had dilated cardiomyopathy. Abstract only accessed.; to: Copied this gene from the Renal tubulopathies panel. In 6 cases reported in PMID: 34607910 (Schlingmann et al 2021) the probands also had dilated cardiomyopathy. The 6 patients with Dilated cardiomyopathy were diagnosed with the condition at ages between 6 months and 14 years old.
Renal tubulopathies v2.62 RRAGD Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype.

As reviewer states PMID: 34607910 (Schlingmann et al 2021) reports 8 cases where patients with hypomagnesaemia were found to have heterozygous (mostly de novo) missense variants in RRAGD. 6 patients also had dilated cardiomyopathy. In addition they report a family with a heterozygous variant in RRAGD that segregated with a kidney phenotype in eight members. Abstract only accessed.; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

As reviewer states PMID: 34607910 (Schlingmann et al 2021) reports 8 cases where patients with hypomagnesaemia were found to have heterozygous (mostly de novo) missense variants in RRAGD. 6 patients also had dilated cardiomyopathy. In addition they report a family with a heterozygous variant in RRAGD that segregated with a kidney phenotype in eight members. The age of onset was 6 months to 24 years.
Dilated and arrhythmogenic cardiomyopathy v1.28 RRAGD Eleanor Williams commented on gene: RRAGD: Update on PMID: 34607910 (Schlingmann et al 2021) - the 6 patients with Dilated cardiomyopathy were diagnosed with the condition at ages between 6 months and 14 years old.
DDG2P v2.78 TERC Eleanor Williams commented on gene: TERC
DDG2P v2.78 RMRP Eleanor Williams commented on gene: RMRP
DDG2P v2.78 COL6A1 Eleanor Williams commented on gene: COL6A1
Intellectual disability v3.1677 EMC1 Eleanor Williams Added comment: Comment on mode of inheritance: 3 more cases of monoallelic variants in patients with an intellectual disability phenotype now reported so the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'
Intellectual disability v3.1677 EMC1 Eleanor Williams Mode of inheritance for gene: EMC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1676 EMC1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: EMC1.
Intellectual disability v3.1676 EMC1 Eleanor Williams commented on gene: EMC1
DDG2P v2.78 EMC1 Eleanor Williams commented on gene: EMC1
Early onset or syndromic epilepsy v2.572 CNKSR2 Eleanor Williams Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892; 25644381; 28098945; 34266427
Early onset or syndromic epilepsy v2.571 CNKSR2 Eleanor Williams commented on gene: CNKSR2
Intellectual disability v3.1676 CNKSR2 Eleanor Williams commented on gene: CNKSR2
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant) in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported. ; to: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant) in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported.
Fetal anomalies v1.904 RAB11A Eleanor Williams Classified gene: RAB11A as Amber List (moderate evidence)
Fetal anomalies v1.904 RAB11A Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber for now, but with a recommendation of GREEN rating following GMS expert review as to whether the brain anomaly/microcephaly phenotype observed in 5 individuals with missense variants in RAB11A is appropriate for this panel.
Fetal anomalies v1.904 RAB11A Eleanor Williams Gene: rab11a has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.903 RAB11A Eleanor Williams Phenotypes for gene: RAB11A were changed from Epilepsy and intellectual disability to microcephaly, HP:0000252; brain anomalies; Intellectual disability, HP:0001249
Fetal anomalies v1.902 RAB11A Eleanor Williams Added comment: Comment on mode of pathogenicity: All missense variants but no functional data available.
Fetal anomalies v1.902 RAB11A Eleanor Williams Mode of pathogenicity for gene: RAB11A was changed from to Other
Fetal anomalies v1.901 RAB11A Eleanor Williams Publications for gene: RAB11A were set to
Fetal anomalies v1.900 RAB11A Eleanor Williams Tag Q3_22_rating tag was added to gene: RAB11A.
Tag Q3_22_expert_review tag was added to gene: RAB11A.
Fetal anomalies v1.900 RAB11A Eleanor Williams changed review comment from: PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant)
in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described. For 3 of the 4 individuals there are brain MRI data which indicate brain abnormalities including partial agenesis of the corpus callosum, or thin corpus collosum.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Both are reported to have microcephaly (degree not stated) and brain anomalies (both with agenesis of corpus callosum, and one with additional abnormal cortical gyration, mylation abnormalites).; to: PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant)
in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described. For 3 of the 4 individuals there are brain MRI data which indicate brain abnormalities including partial agenesis of the corpus callosum, or thin corpus collosum.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Both are reported to have microcephaly (degree not stated) and brain anomalies (both with agenesis of corpus callosum, and one with additional abnormal cortical gyration, myelination abnormalites).
Fetal anomalies v1.900 RAB11A Eleanor Williams commented on gene: RAB11A
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant)
in addition to developing severe ID.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.; to: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant) in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported.
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams Classified gene: RAB11A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 2 patients reported with seizures, 1 each in PMID: 29100083 and PMID: 33875846 but little clinical information.
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams Gene: rab11a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.570 RAB11A Eleanor Williams commented on gene: RAB11A
Intellectual disability v3.1676 RAB11A Eleanor Williams changed review comment from: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.; to: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.
Intellectual disability v3.1676 RAB11A Eleanor Williams changed review comment from: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients. One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.; to: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.
Early onset or syndromic epilepsy v2.570 RAB11A Eleanor Williams gene: RAB11A was added
gene: RAB11A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RAB11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAB11A were set to 29100083; 33875846
Phenotypes for gene: RAB11A were set to Global developmental delay, HP:0001263; Intellectual disability, HP:0001249; seizures
Intellectual disability v3.1676 RAB11A Eleanor Williams Classified gene: RAB11A as Amber List (moderate evidence)
Intellectual disability v3.1676 RAB11A Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber just now, but with a recommendation of GREEN rating following GMS review. There are now 6 unrelated individuals with an intellectual disability phenotype reported and missense variants in this gene. Although there is little clinical data available the number of cases adds weight to this gene-disease association.
Intellectual disability v3.1676 RAB11A Eleanor Williams Gene: rab11a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1675 RAB11A Eleanor Williams Phenotypes for gene: RAB11A were changed from Global developmental delay; Global developmental delay, Intellectual disability; Intellectual disability to Global developmental delay, HP:0001263; Intellectual disability, HP:0001249
Intellectual disability v3.1674 RAB11A Eleanor Williams Publications for gene: RAB11A were set to 29100083
Intellectual disability v3.1673 RAB11A Eleanor Williams Tag Q3_22_rating tag was added to gene: RAB11A.
Intellectual disability v3.1673 RAB11A Eleanor Williams commented on gene: RAB11A
DDG2P v2.78 RAB11A Eleanor Williams commented on gene: RAB11A
Intellectual disability v3.1673 FBXW7 Sarah Leigh edited their review of gene: FBXW7: Changed rating: GREEN
Intellectual disability v3.1673 FBXW7 Sarah Leigh Classified gene: FBXW7 as Amber List (moderate evidence)
Intellectual disability v3.1673 FBXW7 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 v3.1673 FBXW7 Sarah Leigh Gene: fbxw7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1672 FBXW7 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXW7.
Tag Q3_22_MOI tag was added to gene: FBXW7.
Tag Q3_22_phenotype tag was added to gene: FBXW7.
Intellectual disability v3.1672 FBXW7 Sarah Leigh commented on gene: FBXW7
Fetal anomalies v1.900 EDA Rhiannon Mellis reviewed gene: EDA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.900 CHRM3 Rhiannon Mellis gene: CHRM3 was added
gene: CHRM3 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: CHRM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRM3 were set to PMID: 22077972; 31441039; 10944224
Phenotypes for gene: CHRM3 were set to Prune belly syndrome; Megacystis
Review for gene: CHRM3 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Discussed as a potential cause of megacystis. Currently Red on Panelapp CAKUT panel (2016) because at that time there was only 1 reported family and a mouse model. The unpublished data mentioned in that panelapp review (from Adrian Woolf, Manchester) is now published so now 2 families PMID: 22077972; 31441039 plus a mouse model PMID: 10944224. However, prenatal findings (distended bladder and unilateral hydronephrosis) only documented for one individual. More evidence of prenatal phenotype would be helpful.
Sources: Expert Review, Literature
Fetal anomalies v1.900 DEPDC5 Rhiannon Mellis commented on gene: DEPDC5: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Currently rated Green on the following other PanelApp panel(s): Intellectual disability, Genetics epilepsies. Amber on cortical malformations panel.

Details of review:
Previously reviewed as Red because only associated with familial epilepsy without structural brain anomalies (AD - caused by het LOF variants) but data presented by Dr Lara Menzies at CGS Spring Meeting 2021 suggests that there may also be a biallelic phenotype with hypomorphic variants. 5 cases presented from 3 unrelated Irish traveller families with significant polymicrogyria and macrocephaly as well as seizures and severe dev delay. At least 2 of the cases had prenatal features: ventriculomegaly, macrocephaly and IUGR for one, polymicrogyria on MRI for another - fetal MRI done because of FHx of affected child. (Unpublished data)

Liu et al 2020 (PMID: 32848577) report one case with homozygous missense variants in this gene, who had focal cortical dysplasia and seizures from 3yo
Fetal anomalies v1.900 DEPDC5 Rhiannon Mellis reviewed gene: DEPDC5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32848577; Phenotypes: Epilepsy, Structural brain malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.900 ENG Rhiannon Mellis gene: ENG was added
gene: ENG was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: ENG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ENG were set to Telangiectasia, hereditary hemorrhagic, type 1
Review for gene: ENG was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Consistency check because out of 4 known HHT genes EPHB4 and SMAD4 are on the fetal anomalies panel but ACVRL1 and ENG are not.

No specific published reports of ENG variants detected prenatally but correlates with pulmonary AVMs which can present neonatally and can be detected on prenatal US (PMID: 17719943; PMID: 21988128).
Sources: Expert Review, Literature
Fetal anomalies v1.900 ACVRL1 Rhiannon Mellis reviewed gene: ACVRL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 27381467, 32170914; Phenotypes: Telangiectasia, hereditary hemorrhagic, type 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.900 TK2 Rhiannon Mellis reviewed gene: TK2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.900 PIGS Rhiannon Mellis gene: PIGS was added
gene: PIGS was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: PIGS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGS were set to PMID: 30269814
Phenotypes for gene: PIGS were set to Developmental and epileptic encephalopathy 95
Review for gene: PIGS was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Currently red/amber on some other panels but reviewed on Congenital disorders of glycosylation panel as having sufficient evidence for green rating at next major review, in light of this same paper (PMID: 30269814). Three unrelated families reported. Severe neurological phenotype ranging from fetal akinesia to intellectual disability/epileptic encephalopathy. Fetal akinesia phenotype may be relevant for fetal anomalies panel.
Sources: Expert Review, Literature
Fetal anomalies v1.900 MRPS16 Rhiannon Mellis gene: MRPS16 was added
gene: MRPS16 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: MRPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS16 were set to PMID: 28749478
Phenotypes for gene: MRPS16 were set to Combined oxidative phosphorylation deficiency 2
Review for gene: MRPS16 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Amber on mitochondrial/inborn errors of metabolism etc. Not Green on any panel. One previous case reported with "agenesis of the corpus callosum, dysmorphism, and fatal neonatal lactic acidosis. The patient was small at birth, with dysmorphic facies, low-set ears, nonpitting edema of the limbs, brachydactyly, and redundant skin over the neck. She died of intractable metabolic acidosis at age 3 days." PMID:15505824 (2004).

One further fetal case reported by Shamseldin et al. 2018 (PMID: 28749478) with hydrops, very short long bones, and partial ACC
Sources: Expert Review, Literature
Fetal anomalies v1.900 THSD1 Rhiannon Mellis gene: THSD1 was added
gene: THSD1 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: THSD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THSD1 were set to PMID: 28749478; 26036949
Phenotypes for gene: THSD1 were set to Intracerebral aneurysms; ?Hydrops fetalis
Review for gene: THSD1 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene pending more evidence.

Details of review:
Not currently Green on any panels. Amber on Cerebral vascular malformations. (Heterozygous mutations identified in nine families with intracerebral aneurysms plus animal models but unclear on penetrance.)

Shamseldin et al 2018 (PMID: 28749478) report a fetal case with hydrops and a HOMOZYGOUS likely pathogenic variant in THSD1. The same group previously identified this same founder mutation in THSD1 in another 3 families with hydrops/oedema (PMID: 26036949)
Sources: Expert Review, Literature
White matter disorders and cerebral calcification - childhood onset v1.241 SLC35B2 Sarah Leigh Entity copied from Intellectual disability v3.1672
White matter disorders and cerebral calcification - childhood onset v1.241 SLC35B2 Sarah Leigh gene: SLC35B2 was added
gene: SLC35B2 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid
Penetrance for gene: SLC35B2 were set to Complete
Skeletal dysplasia v2.211 SLC35B2 Sarah Leigh Entity copied from Intellectual disability v3.1672
Skeletal dysplasia v2.211 SLC35B2 Sarah Leigh gene: SLC35B2 was added
gene: SLC35B2 was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid
Penetrance for gene: SLC35B2 were set to Complete
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Classified gene: SLC35B2 as Amber List (moderate evidence)
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Added comment: Comment on list classification: The evidence for this gene is sufficient for an amber rating. Although supportive functional evidence is presented in PMID: 35325049, the presence of other variants in both cases reported in this article, means that further evidence is required for SLC35B2 to be rated Green.
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Gene: slc35b2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.900 MYBPC3 Rhiannon Mellis gene: MYBPC3 was added
gene: MYBPC3 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: MYBPC3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: MYBPC3 were set to PMID: 28749478; 19858127
Phenotypes for gene: MYBPC3 were set to Cardiomyopathy; ?Congenital myopathy
Review for gene: MYBPC3 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene pending more evidence.

Currently rated Green on the following other PanelApp panel(s): Various cardiomyopathy panels. Amber on congenital myopathy panel.

Details of review:
Previously only one (AR) case with skeletal muscle phenotype, although is a known cardiomyopathy gene (PMID: 19858127). One fetal case reported by Shamseldin et al 2018 (PMID: 28749478) with hydrops.
Sources: Expert Review, Literature
Fetal anomalies v1.900 NUP88 Rhiannon Mellis reviewed gene: NUP88: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33060286; Phenotypes: fetal akinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.569 CERS1 Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: CERS1.
Fetal anomalies v1.900 CACNA1S Rhiannon Mellis gene: CACNA1S was added
gene: CACNA1S was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: CACNA1S was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1S were set to PMID: 33060286; 28012042
Phenotypes for gene: CACNA1S were set to Congenital myopathy; arthrogryposis
Review for gene: CACNA1S was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Previously only monoallelic variants reported associated with malignant hyperthermia and periodic paralysis but more recently biallelic variants have been associated with congenital myopathy. In Ravenscroft et al 2020 (PMID: 33060286) the reported biallelic variants were VUS but strong suspicion of causality: the proband had polyhydramnios, scalp oedema, bilateral wrist contractures, bilateral talipes and reduced fetal movements, ToP at 26/40. Mild facial dysmorphic features were noted on autopsy, including low anterior hairline, mild hypertelorism and moderate retrognathia. A previous pregnancy was affected with polyhydramnios and reduced fetal movements, delivered at 32/40 due to placental abruption and died at 10 days. On photos the baby had ptosis and broad nasal tip. The biallelic variants segregated within the family (parents and the 2 unaffected sibs all het). No cell lines available for functional studies.
Another study (PMID: 28012042) reports 7 families with congenital myopathy and CACNA1S mutations (both recessive and dominant), of whom 3 had cases with antenatal onset (reduced fetal movements).
Sources: Expert Review, Literature
Early onset or syndromic epilepsy v2.569 FAR1 Sarah Leigh Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154; fatty acyl-CoA reductase 1 deficiency, MONDO:0014510
Early onset or syndromic epilepsy v2.568 FAR1 Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: FAR1.
Fetal anomalies v1.900 NDUFB10 Rhiannon Mellis gene: NDUFB10 was added
gene: NDUFB10 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: NDUFB10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFB10 were set to PMID: 31130284; 28040730
Phenotypes for gene: NDUFB10 were set to Mitochondrial complex I deficiency
Review for gene: NDUFB10 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Not Green on any other panels (Amber/Red because only 1 case reported, with functional studies). Causes Mitochondrial complex 1 deficiency.
One fetal case reported by Monies et al 2019 (PMID: 31130284) with Non-immune hydrops fetalis and died after birth.
The previous reported case on OMIM (from PMID: 28040730) was a female infant with IUGR, hydrops, lung hypoplasia and fetal cardiomyopathy - neonatal death with rapidly progressive lactic acidosis and PM found decreased complex 1 activity in skeletal muscle, heart, liver. Previous child of parents also had hydrops and died on day 1 of life.
Sources: Expert Review, Literature
Fetal anomalies v1.900 FTO Rhiannon Mellis gene: FTO was added
gene: FTO was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to PMID: 31130284; 19559399; 26378117
Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism
Review for gene: FTO was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Not Green on any panels (only 2 families reported to date). On OMIM: Growth retardation, developmental delay, facial dysmorphism. One fetal case reported by Monies et al 2019 (PMID: 31130284) with Dandy-Walker malformation, IUGR, and polyhydramnios. This fits with the phenotype reported in one consanguineous family with 9 affected individuals reported by Boissel 2009 PMID: 19559399. The other reported case is PMID: 26378117 - a homozygous missense variant in FTO was identified in a 21-month old girl who presented with growth retardation, failure to thrive, severely delayed development, Dysmorphic facial features, decreased brain parenchyma, delayed myelination, and a thin corpus callosum.
Sources: Expert Review, Literature
Fetal anomalies v1.900 CACNA1D Rhiannon Mellis reviewed gene: CACNA1D: 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: PMID: 32410215; Phenotypes: PRIMARY ALDOSTERONISM, SEIZURES, AND NEUROLOGIC ABNORMALITIES; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.568 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621; 24782409
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554). Generalized seizures are reported in 20-40% cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842) according to OMIM.
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh Tag Q3_22_rating was removed from gene: XK.
Tag Q3_22_MOI was removed from gene: XK.
Dystonia, chorea or related movement disorder, childhood onset v1.246 XK Sarah Leigh Classified gene: XK as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.246 XK Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.246 XK Sarah Leigh Gene: xk has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.245 XK Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.245
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh gene: XK was added
gene: XK was added to Genetic epilepsy syndromes. Sources: Expert list,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: XK.
Mode of inheritance for gene: XK 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: XK were set to 11761473; 30128557; 8004674; 8619554
Phenotypes for gene: XK were set to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Dystonia, chorea or related movement disorder, childhood onset v1.245 XK Sarah Leigh Tag Q3_22_rating tag was added to gene: XK.
Tag Q3_22_MOI tag was added to gene: XK.
Dystonia, chorea or related movement disorder, childhood onset v1.245 XK Sarah Leigh Classified gene: XK as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.245 XK Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.245 XK Sarah Leigh Gene: xk has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.244 XK Sarah Leigh Publications for gene: XK were set to 11761473; 30128557; 8004674
Dystonia, chorea or related movement disorder, childhood onset v1.243 XK Sarah Leigh reviewed gene: XK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8619554; Phenotypes: ; Mode of inheritance: None
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.79 XK Sarah Leigh reviewed gene: XK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8619554; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v1.900 ASXL3 Rhiannon Mellis edited their review of gene: ASXL3: Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but still limited evidence, support keeping as Amber gene for now.

Details of review:
Previously reviewed as Amber as 2 fetal cases in literature: one from PMID: 32565546 with short CC and metopic synostosis, one from PMID: 29316359 with distal arthrogryposis and cerebellar vermian hypoplasia. Now there is one more fetal case reported with arthrogryposis - PMID: 33820833; Changed publications to: PMID: 33820833; Changed phenotypes to: Arthrogryposis
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.79 XK Sarah Leigh Classified gene: XK as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.79 XK Sarah Leigh Gene: xk has been classified as Green List (High Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.243 XK Sarah Leigh Publications for gene: XK were set to 11761473; 30128557
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.78 XK Sarah Leigh Publications for gene: XK were set to 30128557; 20301528
Fetal anomalies v1.900 NONO Rhiannon Mellis reviewed gene: NONO: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 31680349; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare anaemia v1.41 XK Sarah Leigh Phenotypes for gene: XK were changed from McLeod syndrome with or without chronic granulomatous disease,OMIM:300842 to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Dystonia, chorea or related movement disorder, childhood onset v1.242 XK Sarah Leigh Publications for gene: XK were set to 11761473
Fetal anomalies v1.900 FOXP2 Rhiannon Mellis reviewed gene: FOXP2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28976722; Phenotypes: Speech-language disorder, structural abnormalities of basal ganglia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v1.28 MYZAP Aleš Maver changed review comment from: Two independent publications reported the presence of biallelic loss-of-function variants in MYZAP gene in three families altogether with recessive dilated cardiomyopathy (DCM) (PMID:34899865 and doi:10.1101/mcs.a006221). Altogether, 8 patients with DCM and biallelic LOF variants are reported in the three published families.
Functional studies published previously linked the loss of MYZAP protein to DCM in zebrafish (PMID:20093627).
Functional studies of the variant reported in 10.1101/mcs.a006221 have shown that the variant led to lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction in the patient-derived iPSC cardiomyocytes.
Sources: Other; to: Two independent publications reported the presence of biallelic loss-of-function variants in MYZAP gene in three families altogether with recessive dilated cardiomyopathy (DCM) (PMID:34899865 and PMID:35840178). Altogether, 8 patients with DCM and biallelic LOF variants are reported in the three published families.
Functional studies published previously linked the loss of MYZAP protein to DCM in zebrafish (PMID:20093627).
Functional studies of the variant reported in PMID:35840178 have shown that the variant led to lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction in the patient-derived iPSC cardiomyocytes.
Sources: Other
Fetal anomalies v1.900 AGT Rhiannon Mellis gene: AGT was added
gene: AGT was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGT were set to PMID: 28976722
Phenotypes for gene: AGT were set to Renal dysgenesis
Review for gene: AGT was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene pending more evidence.

Currently rated Green on the following other PanelApp panel(s): CAKUT and unexplained kidney failure in young people

Details of review:
Fu et al 2018 (PMID: 28976722) report one fetal case with Right multicystic dysplastic kidney
Sources: Literature, Expert Review
Dilated and arrhythmogenic cardiomyopathy v1.28 MYZAP Aleš Maver changed review comment from: Two independent publications reported the presence of biallelic loss-of-function variants in MYZAP gene in, altogether, three families (altogether 8 patients with DCM) with recessive dilated cardiomyopathy (DCM) (34899865;doi:10.1101/mcs.a006221).
Functional studies published previously linked the loss of MYZAP protein to DCM in zebrafish (PMID:20093627).
Functional studies of the variant reported in 10.1101/mcs.a006221 have shown that the variant led to lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction in the patient-derived iPSC cardiomyocytes.
Sources: Other; to: Two independent publications reported the presence of biallelic loss-of-function variants in MYZAP gene in three families altogether with recessive dilated cardiomyopathy (DCM) (PMID:34899865 and doi:10.1101/mcs.a006221). Altogether, 8 patients with DCM and biallelic LOF variants are reported in the three published families.
Functional studies published previously linked the loss of MYZAP protein to DCM in zebrafish (PMID:20093627).
Functional studies of the variant reported in 10.1101/mcs.a006221 have shown that the variant led to lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction in the patient-derived iPSC cardiomyocytes.
Sources: Other
Dilated and arrhythmogenic cardiomyopathy v1.28 MYZAP Aleš Maver gene: MYZAP was added
gene: MYZAP was added to Dilated cardiomyopathy - adult and teen. Sources: Other
Mode of inheritance for gene: MYZAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYZAP were set to 34899865; doi:10.1101/mcs.a006221
Phenotypes for gene: MYZAP were set to Dilated cardiomyopathy
Penetrance for gene: MYZAP were set to unknown
Mode of pathogenicity for gene: MYZAP 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: MYZAP was set to RED
Added comment: Two independent publications reported the presence of biallelic loss-of-function variants in MYZAP gene in, altogether, three families (altogether 8 patients with DCM) with recessive dilated cardiomyopathy (DCM) (34899865;doi:10.1101/mcs.a006221).
Functional studies published previously linked the loss of MYZAP protein to DCM in zebrafish (PMID:20093627).
Functional studies of the variant reported in 10.1101/mcs.a006221 have shown that the variant led to lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction in the patient-derived iPSC cardiomyocytes.
Sources: Other
Fetal anomalies v1.900 ASPH Rhiannon Mellis reviewed gene: ASPH: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28976722; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.900 ST3GAL5 Rhiannon Mellis reviewed gene: ST3GAL5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28976722; Phenotypes: Infantile epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.247 PTPRQ Barbara Vona reviewed gene: PTPRQ: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 29309402, PMID: 31655630; Phenotypes: DEAFNESS, AUTOSOMAL DOMINANT 73, DFNA73; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1671 CNKSR2 Eleanor Williams Phenotypes for gene: CNKSR2 were changed from ntellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909 to Intellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Intellectual disability v3.1670 CNKSR2 Eleanor Williams Publications for gene: CNKSR2 were set to
Intellectual disability v3.1669 CNKSR2 Eleanor Williams Phenotypes for gene: CNKSR2 were changed from INTELLECTUAL DISABILITY WITH EPILEPSY; X-linked intellectual disability; XLID to ntellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Early onset or syndromic epilepsy v2.566 CNKSR2 Eleanor Williams Phenotypes for gene: CNKSR2 were changed from Mental retardation, X-linked, syndromic, Houge type 301008 to Intellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Early onset or syndromic epilepsy v2.565 CNKSR2 Eleanor Williams Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892; 25644381; 28098945
DDG2P v2.78 CNKSR2 Eleanor Williams commented on gene: CNKSR2
Primary immunodeficiency or monogenic inflammatory bowel disease v2.573 TPP2 Eleanor Williams Phenotypes for gene: TPP2 were changed from Tripeptidyl-Peptidase II Deficiency; TPP2 deficiency; Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome; immune thrombocytopenia and autoimmune hemolytic anemia; Evans syndrome; Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections; Diseases of Immune Dysregulation to Tripeptidyl-Peptidase II Deficiency; TPP2 deficiency; Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome; immune thrombocytopenia and autoimmune hemolytic anemia; Evans syndrome; Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections; Diseases of Immune Dysregulation; Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
Intellectual disability v3.1668 TPP2 Eleanor Williams commented on gene: TPP2: As the first presentation for patients is features of immune deficiency and autoimmunity, seeking clinical input before proposing a rating for this gene on the intellectual disability panel.
Intellectual disability v3.1668 TPP2 Eleanor Williams Publications for gene: TPP2 were set to
Intellectual disability v3.1667 TPP2 Eleanor Williams reviewed gene: TPP2: Rating: ; Mode of pathogenicity: None; Publications: 33586135, 25414442, 25525876, 30533531; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1667 TPP2 Eleanor Williams gene: TPP2 was added
gene: TPP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TPP2 were set to Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
DDG2P v2.78 TPP2 Eleanor Williams changed review comment from: This panel reflects the DD panel in the Gene2Phenotype resource and will be updated shortly from that resource where it currently has a 'definitive' level of evidence.; to: This panel reflects the DD panel in the Gene2Phenotype resource and will be updated shortly from that resource where it currently has a 'definitive' level of evidence.
DDG2P v2.78 TPP2 Eleanor Williams commented on gene: TPP2
DDG2P v2.78 RAP1GDS1 Eleanor Williams Tag curated_removed tag was added to gene: RAP1GDS1.
DDG2P v2.78 RAP1GDS1 Eleanor Williams changed review comment from: This panel reflects the DD panel in the Gene2Phenotype resource and will be updated based on updates to that resource. The expert reviewer has also reviewed this gene on the Intellectual disability panel in PanelApp, which is part of the Paediatric disorders super panel so this gene will not be missed out of the super panel.; to: This panel reflects the DD panel in the Gene2Phenotype resource and will be updated based on updates to that resource. It is not currently listed on the DD panel. The expert reviewer has also reviewed this gene on the Intellectual disability panel in PanelApp, which is part of the Paediatric disorders super panel so this gene will not be missed out of the super panel.
Intellectual disability v3.1666 TAF4 Eleanor Williams Classified gene: TAF4 as Amber List (moderate evidence)
Intellectual disability v3.1666 TAF4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. There are 3 cases reported but in one the phenotype is reported as autism, and in the other two there is no information as to the severity. The mouse knockout shows there is an effect of loss of TAF4 but the phenotype is perhaps not specific enough to add weight to rating of this gene for intellectual disability.
Intellectual disability v3.1666 TAF4 Eleanor Williams Gene: taf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1665 TAF4 Eleanor Williams Mode of inheritance for gene: TAF4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1664 TAF4 Eleanor Williams Publications for gene: TAF4 were set to 33875846
Intellectual disability v3.1663 TAF4 Eleanor Williams Phenotypes for gene: TAF4 were changed from Developmental delay to Developmental disorder
Intellectual disability v3.1662 TAF4 Eleanor Williams commented on gene: TAF4: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 - Bertoli-Avella et al 2021 - identified two de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and one with intellectual disability and one with delayed speech and language development with global developmental delay.

PMID: 28191890 - Kosmicki et al 2017 - report a child with autism with an indel in TAF4 leading to a frameshift. No phenotypic details provided.

PMID: 27026076 - Langer et al 2016 - Taf4a−/− (gene encoding Taf4) mouse embryos survive until E9.5, but show severe growth retardation and specific defects in anterior and ventral patterning and morphogenesis.
Fetal anomalies v1.900 MANBA Rhiannon Mellis reviewed gene: MANBA: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33249554; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1662 TAF4 Eleanor Williams Tag curated_removed was removed from gene: TAF4.
Intellectual disability v3.1662 TAF4 Eleanor Williams Entity copied from DDG2P v2.78
Intellectual disability v3.1662 TAF4 Eleanor Williams gene: TAF4 was added
gene: TAF4 was added to Intellectual disability. Sources: Expert Review Removed,Literature
curated_removed tags were added to gene: TAF4.
Mode of inheritance for gene: TAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF4 were set to 33875846
Phenotypes for gene: TAF4 were set to Developmental delay
Penetrance for gene: TAF4 were set to unknown
DDG2P v2.78 TAF4 Eleanor Williams commented on gene: TAF4
DDG2P v2.78 TAF4 Eleanor Williams Tag curated_removed tag was added to gene: TAF4.
DDG2P v2.78 TAF4 Eleanor Williams Classified gene: TAF4 as No list
DDG2P v2.78 TAF4 Eleanor Williams Gene: taf4 has been removed from the panel.
DDG2P v2.77 RPGRIP1 Eleanor Williams commented on gene: RPGRIP1
DDG2P v2.77 RASA1 Eleanor Williams commented on gene: RASA1
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Tag Q3_22_rating tag was added to gene: RAP1GDS1.
Tag Q3_22_expert_review tag was added to gene: RAP1GDS1.
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Classified gene: RAP1GDS1 as Amber List (moderate evidence)
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. There are now 4 families reported with the same splice site variant and a similar phenotype but intellectual disability is not seen in all probands. 2 of the families come from the same region. The ancestry of the other 2 families is not known. There is one additional case with a different 1bp deletion variant in RAP1GDS1 is also reported with ID as part of the phenotype. The expert reviewer proposes this gene should be green, and it also green on the PanelApp Australia Intellectual disability panel. Therefore the recommendation is for GREEN rating following GMS consideration and expert review.
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Gene: rap1gds1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1660 RAP1GDS1 Eleanor Williams commented on gene: RAP1GDS1
Skeletal dysplasia v2.210 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from Short stature; skeletal defects; Intellectual disability; Speech delay; macrocephaly; dysmorphism to Congenital disorder of glycosylation, type Iw, autosomal dominant, OMIM:619714
Skeletal dysplasia v2.209 STT3A Arina Puzriakova Classified gene: STT3A as Amber List (moderate evidence)
Skeletal dysplasia v2.209 STT3A Arina Puzriakova Added comment: Comment on list classification: Congenital disorder of glycosylation due to monoallelic variants in STT3A has been identified in at least 16 patients from 9 families (PMID: 34653363). Phenotypes included skeletal abnormalities in 10/16 subjects. Overall this supports a Green gene rating with a 'monoallelic' MOI on this panel at the next GMS panel review.
Skeletal dysplasia v2.209 STT3A Arina Puzriakova Gene: stt3a has been classified as Amber List (Moderate Evidence).
DDG2P v2.77 RAP1GDS1 Eleanor Williams commented on gene: RAP1GDS1
Skeletal dysplasia v2.208 STT3A Arina Puzriakova Tag Q3_22_rating tag was added to gene: STT3A.
Tag Q3_22_NHS_review tag was added to gene: STT3A.
Intellectual disability v3.1660 STT3A Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: STT3A.
Intellectual disability v3.1660 ALKBH8 Arina Puzriakova Publications for gene: ALKBH8 were set to 31130284; 31079898; 33544954; 34757492
Intellectual disability v3.1659 ALKBH8 Arina Puzriakova edited their review of gene: ALKBH8: Changed publications to: 31079898, 33544954, 34757492, 35571055; Changed phenotypes to: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Intellectual disability v3.1659 ALKBH8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ALKBH8.
Intellectual disability v3.1659 ALKBH8 Arina Puzriakova reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504; Phenotypes: 31079898, 33544954, 34757492, 35571055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.564 ALKBH8 Arina Puzriakova Publications for gene: ALKBH8 were set to 31130284; 31079898
Early onset or syndromic epilepsy v2.563 ALKBH8 Arina Puzriakova reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079898, 33544954, 34757492, 35571055; Phenotypes: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.77 MYH6 Eleanor Williams changed review comment from: This gene needs further investigation as to the rating when this panel is updated from Gene2Phenotype DD panel.; to: This gene needs further investigation as to the rating when this panel is updated from Gene2Phenotype DD panel. Q3_22 tags added to flag it only.
DDG2P v2.77 MYH6 Eleanor Williams Tag Q3_22_rating tag was added to gene: MYH6.
Tag Q3_22_expert_review tag was added to gene: MYH6.
DDG2P v2.77 KPNA3 Eleanor Williams Tag curated_removed tag was added to gene: KPNA3.
DDG2P v2.77 KPNA3 Eleanor Williams Classified gene: KPNA3 as No list
DDG2P v2.77 KPNA3 Eleanor Williams Gene: kpna3 has been removed from the panel.
Fetal anomalies v1.900 UNC13D Rhiannon Mellis gene: UNC13D was added
gene: UNC13D was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: UNC13D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC13D were set to PMID: 33249554
Phenotypes for gene: UNC13D were set to Pancytopenia; ?Hydrops fetalis
Review for gene: UNC13D was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Currently rated Green on the following other PanelApp panel(s): primary immunodeficiency

Details of review:
One fetal case reported in Diderich et al 2020 (PMID: 33249554) with hydrops, presumed secondary to fetal anaemia.
Sources: Literature, Expert Review
Fetal anomalies v1.900 C1QBP Rhiannon Mellis reviewed gene: C1QBP: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32304219; Phenotypes: Combined oxidative phosphorylation deficiency 33, Cardiomyopathy, Myopathy, Metabolic acidosis, Ologohydramnios; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.900 SERPINA11 Rhiannon Mellis gene: SERPINA11 was added
gene: SERPINA11 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINA11 were set to PMID: 31742715; 28749478
Phenotypes for gene: SERPINA11 were set to ?Hydrops fetalis
Review for gene: SERPINA11 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene to watch for further evidence.

Not currently rated Green on any other PanelApp panel(s).

Details of review:
No OMIM disease association currently. Reported as a novel genotype-phenotype association in Aggarwal 2020 (PMID: 31742715) in a fetus with homozygous nonsense variant. Fetus presented with pericardial effusion and on post-mortem was found to have serous cavity effusions, and generalised blebs of gelatinous material on the visceral surfaces. Histopathology and stains showed derangement of ECM and collagen fibres. Consanguineous couple with one similarly affected previous pregnancy. This gene is also reported in Shamseldin et al 2018 (PMID: 28749478) as a candidate gene in a fetus with hydrops.
Sources: Expert Review, Literature
Fetal anomalies v1.900 LOX Rhiannon Mellis gene: LOX was added
gene: LOX was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: LOX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOX were set to PMID: 31742715
Phenotypes for gene: LOX were set to Aortopathy
Review for gene: LOX was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Currently rated Green on the following other PanelApp panel(s): familial thoracic aortic aneurysm

Details of review:
Reported as a novel genotype-phenotype association in Aggarwal et al 2020 (PMID: 31742715), in a fetus with homozygous missense variants. Heterozygous variants in this gene are known to cause thoracic aortic aneurysm. The fetus presented with unexplained IUD and on post-mortem had: Excessive skin folds, emphysematous bullae on lung surface, Facial dysmorphism, distal joint contractures, internal haemorrhages. Histopathology and special stains confirmed degradation of collagen and elastin in the aorta, pleura and skin. If we are going to add to panel suggest putting MOI as biallelic only (and accept that this would be an incidental finding for carrier parents that would lead to them needing monitoring for aortic aneurysm)
Sources: Expert Review, Literature
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.77 XK Sarah Leigh Phenotypes for gene: XK were changed from Chorea; Dystonia; Cognitive impairment; Myopathy; Cardiomyopathy; Peripheral neuropathy; Seizures; Acanthocytosis; Compensated haemolysis to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Dystonia, chorea or related movement disorder, childhood onset v1.241 XK Sarah Leigh Phenotypes for gene: XK were changed from McLeod syndrome with or without chronic granulomatous disease MIM#300842 to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Intellectual disability v3.1659 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Early onset or syndromic epilepsy v2.563 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Intellectual disability v3.1658 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Developmental and epileptic encephalopathy 55, OMIM:617599
Early onset or syndromic epilepsy v2.562 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Developmental and epileptic encephalopathy 55, OMIM:617599
Early onset or syndromic epilepsy v2.561 PIGP Arina Puzriakova Tag watchlist was removed from gene: PIGP.
Intellectual disability v3.1657 KAT8 Arina Puzriakova Phenotypes for gene: KAT8 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism to Li-Ghorgani-Weisz-Hubshman syndrome, OMIM:618974; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Early onset or syndromic epilepsy v2.561 KAT8 Arina Puzriakova Phenotypes for gene: KAT8 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism to Li-Ghorgani-Weisz-Hubshman syndrome, OMIM:618974; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Early onset or syndromic epilepsy v2.560 KAT8 Arina Puzriakova Tag watchlist_moi tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.560 ASNS Arina Puzriakova Publications for gene: ASNS were set to 24139043; 25227173; 29375865; 24139043; 27469131
Intellectual disability v3.1656 TAF8 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: TAF8.
Hereditary spastic paraplegia, childhood onset v2.145 TAF8 Arina Puzriakova Entity copied from Intellectual disability v3.1656
Hereditary spastic paraplegia, childhood onset v2.145 TAF8 Arina Puzriakova gene: TAF8 was added
gene: TAF8 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: TAF8.
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to 29648665; 35759269
Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Penetrance for gene: TAF8 were set to unknown
Early onset or syndromic epilepsy v2.559 TAF8 Arina Puzriakova Entity copied from Intellectual disability v3.1656
Early onset or syndromic epilepsy v2.559 TAF8 Arina Puzriakova gene: TAF8 was added
gene: TAF8 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: TAF8.
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to 29648665; 35759269
Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Penetrance for gene: TAF8 were set to unknown
Intellectual disability v3.1656 TAF8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TAF8.
Intellectual disability v3.1656 TAF8 Arina Puzriakova Classified gene: TAF8 as Amber List (moderate evidence)
Intellectual disability v3.1656 TAF8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Jana Jezkova. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

TAF8 is associated with a relevant phenotype in OMIM (MIM# 619972) but is not yet listed in G2P.

8 individuals from 5 families have been reported in literature (PMIDs: 29648665; 35759269). Four families from different ethnic backgrounds harboured the same c.781-1G>A homozygous variant while sequencing in a sib pair revealed different compound het splice variants (c.45+4A>G and c.489G>A) in the TAF8 gene. Patients presented with an overlapping phenotype including microcephaly (8/8), DD and ID (8/8), spasticity (7/8), and seizures (6/8). Brain MRI have shown hypoplastic corpus callosum, hypomyelination, enlarged ventricles in most subjects, and additionally generalised brain atrophy in two sibs.
Intellectual disability v3.1656 TAF8 Arina Puzriakova Gene: taf8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1655 TAF8 Arina Puzriakova Publications for gene: TAF8 were set to PMID: 35759269
Intellectual disability v3.1654 TAF8 Arina Puzriakova Phenotypes for gene: TAF8 were changed from severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Fetal anomalies v1.900 TMEM70 Arina Puzriakova Publications for gene: TMEM70 were set to
Fetal anomalies v1.899 TMEM70 Arina Puzriakova Phenotypes for gene: TMEM70 were changed from MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 2 to IUGR; Oligohydramnios; Anhydramnios; Cardiomyopathy
Fetal anomalies v1.898 TMEM70 Arina Puzriakova Classified gene: TMEM70 as Amber List (moderate evidence)
Fetal anomalies v1.898 TMEM70 Arina Puzriakova Added comment: Comment on list classification: Following clinical review, it was agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.898 TMEM70 Arina Puzriakova Gene: tmem70 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.897 TMEM70 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TMEM70.
Tag Q3_22_NHS_review tag was added to gene: TMEM70.
Fetal anomalies v1.897 SPTA1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber in with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype (added watchlist tag); to: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype (added watchlist tag)
Fetal anomalies v1.897 SPTA1 Arina Puzriakova Classified gene: SPTA1 as Amber List (moderate evidence)
Fetal anomalies v1.897 SPTA1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber in with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype (added watchlist tag)
Fetal anomalies v1.897 SPTA1 Arina Puzriakova Gene: spta1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.896 SPTA1 Arina Puzriakova Publications for gene: SPTA1 were set to PMID: 34132406; PMID: 31333484
Fetal anomalies v1.895 SPTA1 Arina Puzriakova Tag watchlist tag was added to gene: SPTA1.
Fetal anomalies v1.895 PLOD3 Arina Puzriakova Publications for gene: PLOD3 were set to PMID: 18834968; PMID: 33743358
Fetal anomalies v1.894 PLOD3 Arina Puzriakova Classified gene: PLOD3 as Amber List (moderate evidence)
Fetal anomalies v1.894 PLOD3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber in view of two unrelated cases presenting with a fetal phenotype reported to date.
Fetal anomalies v1.894 PLOD3 Arina Puzriakova Gene: plod3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.893 PLOD3 Arina Puzriakova Phenotypes for gene: PLOD3 were changed from Lysyl hydroxylase 3 deficiency; IUGR; Contractures to Lysyl hydroxylase 3 deficiency, OMIM:612394; IUGR; Contractures
Fetal anomalies v1.892 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093 to Cardiac valvular defect, developmental, OMIM:212093; Cardiomyopathy; Congenital heart malformations
Fetal anomalies v1.891 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 27799408; 33645542
Fetal anomalies v1.890 PLD1 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: PLD1.
Fetal anomalies v1.890 NMNAT2 Arina Puzriakova Publications for gene: NMNAT2 were set to 31136762; 31132363; 23082226
Paediatric or syndromic cardiomyopathy v1.76 NEXN Arina Puzriakova Phenotypes for gene: NEXN were changed from Cardiomyopathy, dilated, 1CC; Cardiomyopathy, familial hypertrophic, 20, to Cardiomyopathy, dilated, 1CC, OMIM:613122; Cardiomyopathy, hypertrophic, 20, OMIM:613876
Dilated and arrhythmogenic cardiomyopathy v1.28 NEXN Arina Puzriakova Phenotypes for gene: NEXN were changed from Cardiomyopathy, dilated, 1CC (613122); Cardiomyopathy, hypertrophic, 20 (613876); Cardiomyopathy, dilated, 1CC to Cardiomyopathy, dilated, 1CC, OMIM:613122
Dilated Cardiomyopathy and conduction defects v1.78 NEXN Arina Puzriakova Phenotypes for gene: NEXN were changed from Cardiomyopathy, hypertrophic, 20 (613876); Cardiomyopathy, dilated, 1CC (613122); Cardiomyopathy, dilated, 1CC to Cardiomyopathy, dilated, 1CC, OMIM:613122
Hypertrophic cardiomyopathy v2.41 NEXN Arina Puzriakova Phenotypes for gene: NEXN were changed from Cardiomyopathy, dilated, 1CC (613122); Cardiomyopathy, familial hypertrophic, 20, ; Cardiomyopathy, hypertrophic, 20 (613876) to Cardiomyopathy, hypertrophic, 20, OMIM:613876
Fetal anomalies v1.889 NEXN Arina Puzriakova Phenotypes for gene: NEXN were changed from Cardiomyopathy to Cardiomyopathy, dilated, 1CC, OMIM:613122; Cardiomyopathy, hypertrophic, 20, OMIM:613876
Fetal anomalies v1.888 NEXN Arina Puzriakova Publications for gene: NEXN were set to PMID: 32058062; PMID: 33027564
Fetal anomalies v1.887 NEXN Arina Puzriakova Classified gene: NEXN as Amber List (moderate evidence)
Fetal anomalies v1.887 NEXN Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber in view of two unrelated cases presenting with a fetal phenotype reported to date (added watchlist tag).
Fetal anomalies v1.887 NEXN Arina Puzriakova Gene: nexn has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.886 NEXN Arina Puzriakova Tag watchlist tag was added to gene: NEXN.
Fetal anomalies v1.886 NDUFB11 Arina Puzriakova Classified gene: NDUFB11 as Amber List (moderate evidence)
Fetal anomalies v1.886 NDUFB11 Arina Puzriakova Added comment: Comment on list classification: Following clinical review, it was agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.886 NDUFB11 Arina Puzriakova Gene: ndufb11 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.885 NDUFB11 Arina Puzriakova Publications for gene: NDUFB11 were set to
Fetal anomalies v1.884 NDUFB11 Arina Puzriakova Phenotypes for gene: NDUFB11 were changed from MICROPHTHALMIA WITH LINEAR SKIN DEFECTS SYNDROME to Linear skin defects with multiple congenital anomalies 3, OMIM:300952; Cardiomyopathy; Agenesis of corpus callosum (ACC)
Mosaic skin disorders - Deep sequencing v1.23 NDUFB11 Arina Puzriakova Mode of inheritance for gene: NDUFB11 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v1.883 NDUFB11 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB11.
Tag Q3_22_NHS_review tag was added to gene: NDUFB11.
Intellectual disability v3.1653 MED13L Arina Puzriakova Publications for gene: MED13L were set to 23403903
Clefting v2.70 MED13L Arina Puzriakova Phenotypes for gene: MED13L were changed from Mental retardation and distinctive facial features with or without cardiac defects, 616789; MRFACD; Cleft palate to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789; MRFACD; Cleft palate
Fetal anomalies v1.883 MED13L Arina Puzriakova Publications for gene: MED13L were set to
Fetal anomalies v1.882 MED13L Arina Puzriakova Tag Q3_22_rating tag was added to gene: MED13L.
Tag Q3_22_NHS_review tag was added to gene: MED13L.
Intellectual disability v3.1652 MED13L Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789
Fetal anomalies v1.882 MED13L Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789
Fetal anomalies v1.881 MED13L Arina Puzriakova Classified gene: MED13L as Amber List (moderate evidence)
Fetal anomalies v1.881 MED13L Arina Puzriakova Added comment: Comment on list classification: Following clinical review, it was agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.881 MED13L Arina Puzriakova Gene: med13l has been classified as Amber List (Moderate Evidence).
DDG2P v2.76 HYDIN Dmitrijs Rots reviewed gene: HYDIN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pulmonary arterial hypertension v2.23 TBX4 Sarah Leigh reviewed gene: TBX4: Rating: ; Mode of pathogenicity: Other; Publications: 35852389; Phenotypes: ; Mode of inheritance: None
Pulmonary arterial hypertension v2.23 TBX4 Sarah Leigh Publications for gene: TBX4 were set to 23592887; 27587546; 27694411
Optic neuropathy v2.72 SPG7 Ivone Leong edited their review of gene: SPG7: Added comment: Based on the expert review from Penny Clouston (Oxford) and recent literature the MOI should be changed from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal".; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Optic neuropathy v2.72 SPG7 Ivone Leong Tag Q3_21_MOI was removed from gene: SPG7.
Tag Q3_21_NHS_review was removed from gene: SPG7.
Tag Q3_22_MOI tag was added to gene: SPG7.
Tag Q3_22_NHS_review tag was added to gene: SPG7.
Optic neuropathy v2.72 SPG7 Ivone Leong Tag Q3_21_MOI tag was added to gene: SPG7.
Tag Q3_21_NHS_review tag was added to gene: SPG7.
Optic neuropathy v2.72 SPG7 Ivone Leong Phenotypes for gene: SPG7 were changed from SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE, 607259 to SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE, OMIM:607259; autosomal dominant optic atroph, MONDO:0020250
Optic neuropathy v2.71 SPG7 Ivone Leong Added comment: Comment on publications: New publications added
Optic neuropathy v2.71 SPG7 Ivone Leong Publications for gene: SPG7 were set to 9635427; 23065789; 22964162; 25034272
DDG2P v2.76 PMS2 Eleanor Williams commented on gene: PMS2
DDG2P v2.76 MYH6 Eleanor Williams commented on gene: MYH6
Hereditary spastic paraplegia, childhood onset v2.144 KPNA3 Eleanor Williams Classified gene: KPNA3 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.144 KPNA3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation of GREEN rating following GMS review.
Hereditary spastic paraplegia, childhood onset v2.144 KPNA3 Eleanor Williams Gene: kpna3 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.143 KPNA3 Eleanor Williams Tag Q3_21_rating was removed from gene: KPNA3.
Tag Q3_22_rating tag was added to gene: KPNA3.
Hereditary spastic paraplegia, childhood onset v2.143 KPNA3 Eleanor Williams Tag Q3_21_rating tag was added to gene: KPNA3.
Hereditary spastic paraplegia, childhood onset v2.143 KPNA3 Eleanor Williams Phenotypes for gene: KPNA3 were changed from Infantile onset spastic paraplegia; developmental delay to autosomal dominant pure spastic paraplegia, MONDO:0015088
Hereditary spastic paraplegia, childhood onset v2.142 KPNA3 Eleanor Williams Publications for gene: KPNA3 were set to PMID: 34564892
Hereditary spastic paraplegia, childhood onset v2.141 KPNA3 Eleanor Williams Mode of inheritance for gene: KPNA3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary spastic paraplegia, childhood onset v2.140 KPNA3 Eleanor Williams reviewed gene: KPNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34564892; Phenotypes: autosomal dominant pure spastic paraplegia, MONDO:0015088; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v2.76 KPNA3 Eleanor Williams commented on gene: KPNA3
DDG2P v2.76 DSPP Eleanor Williams commented on gene: DSPP
DDG2P v2.76 BFSP2 Eleanor Williams commented on gene: BFSP2
DDG2P v2.76 ATG7 Eleanor Williams commented on gene: ATG7
DDG2P v2.76 AR Eleanor Williams Tag Q3_22_rating tag was added to gene: AR.
Tag Q3_22_expert_review tag was added to gene: AR.
DDG2P v2.76 AR Eleanor Williams commented on gene: AR
DDG2P v2.76 XPNPEP3 Eleanor Williams commented on gene: XPNPEP3
DDG2P v2.76 XPNPEP3 Eleanor Williams Tag Q1_22_rating was removed from gene: XPNPEP3.
DDG2P v2.76 TMEM260 Eleanor Williams commented on gene: TMEM260
DDG2P v2.76 TMEM260 Eleanor Williams Tag Q4_21_rating was removed from gene: TMEM260.
DDG2P v2.76 PEX6 Eleanor Williams commented on gene: PEX6
DDG2P v2.76 PEX6 Eleanor Williams Tag Q1_22_MOI was removed from gene: PEX6.
DDG2P v2.76 FBN2 Eleanor Williams commented on gene: FBN2
DDG2P v2.76 FBN2 Eleanor Williams Tag Q2_21_MOI was removed from gene: FBN2.
DDG2P v2.76 EDNRB Eleanor Williams commented on gene: EDNRB
Optic neuropathy v2.70 SPG7 Penny Clouston reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32548275, 33841295; Phenotypes: Dominnat optic atrophy; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - childhood onset v1.240 TWNK Arina Puzriakova commented on gene: TWNK: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
White matter disorders and cerebral calcification - childhood onset v1.240 SLC25A4 Arina Puzriakova commented on gene: SLC25A4: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Stickler syndrome v2.27 COL11A2 Arina Puzriakova commented on gene: COL11A2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Skeletal dysplasia v2.208 SNRPB Arina Puzriakova commented on gene: SNRPB
Skeletal dysplasia v2.208 FGFR2 Arina Puzriakova commented on gene: FGFR2
Skeletal dysplasia v2.208 COL11A2 Arina Puzriakova commented on gene: COL11A2
Possible mitochondrial disorder, nuclear genes v1.94 DNM2 Arina Puzriakova commented on gene: DNM2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Mitochondrial DNA maintenance disorder v1.10 DNM2 Arina Puzriakova commented on gene: DNM2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Mitochondrial disorders v2.117 DNM2 Arina Puzriakova commented on gene: DNM2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.44 TTN Arina Puzriakova commented on gene: TTN: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.44 SYNE1 Arina Puzriakova commented on gene: SYNE1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Limb disorders v2.79 LRP4 Arina Puzriakova commented on gene: LRP4
Limb disorders v2.79 LMBR1 Arina Puzriakova commented on gene: LMBR1
Intellectual disability v3.1651 MAT1A Arina Puzriakova commented on gene: MAT1A: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Intellectual disability v3.1651 GJC2 Arina Puzriakova commented on gene: GJC2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Likely inborn error of metabolism v2.263 EXT1 Arina Puzriakova commented on gene: EXT1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Likely inborn error of metabolism v2.263 DHTKD1 Arina Puzriakova commented on gene: DHTKD1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Distal myopathies v1.48 TTN Arina Puzriakova commented on gene: TTN: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Congenital myopathy v2.89 LMNA Arina Puzriakova commented on gene: LMNA: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Congenital muscular dystrophy v2.31 LMNA Arina Puzriakova commented on gene: LMNA: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Congenital disorders of glycosylation v2.92 EXT1 Arina Puzriakova commented on gene: EXT1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Clefting v2.69 POLR1D Arina Puzriakova commented on gene: POLR1D
Clefting v2.69 COL2A1 Arina Puzriakova commented on gene: COL2A1
Clefting v2.69 COL11A2 Arina Puzriakova commented on gene: COL11A2
Clefting v2.69 COL11A1 Arina Puzriakova commented on gene: COL11A1
Bilateral congenital or childhood onset cataracts v2.110 COL11A1 Arina Puzriakova commented on gene: COL11A1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Arthrogryposis v3.161 PIEZO2 Arina Puzriakova commented on gene: PIEZO2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Arthrogryposis v3.161 FGFR2 Arina Puzriakova commented on gene: FGFR2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Arthrogryposis v3.161 DNM2 Arina Puzriakova commented on gene: DNM2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
DDG2P v2.76 CLP1 Eleanor Williams commented on gene: CLP1
DDG2P v2.76 CLP1 Eleanor Williams Tag Q2_21_rating was removed from gene: CLP1.
DDG2P v2.76 ATAD3A Eleanor Williams Tag Q3_21_MOI was removed from gene: ATAD3A.
DDG2P v2.76 ATAD3A Eleanor Williams commented on gene: ATAD3A
Early onset or syndromic epilepsy v2.558 CRELD1 Ivone Leong Added comment: Comment on phenotypes: Changed from "neurodevelopmental disorder;treatment resistant epileptic seizures;mild to severe developmental and cognitive delays;adrenal insufficiency;severe bilateral neural hearing loss;immature eye development;accuse respiratory distress and submucosal cleft palate" to "Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate" for Natalie Trump (Congenica) as the first option was entered by mistake.
Early onset or syndromic epilepsy v2.558 CRELD1 Ivone Leong Phenotypes for gene: CRELD1 were changed from neurodevelopmental disorder; treatment resistant epileptic seizures; mild to severe developmental and cognitive delays; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; accuse respiratory distress and submucosal cleft palate to Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate
Early onset or syndromic epilepsy v2.557 CRELD1 Ivone Leong Added comment: Comment on mode of inheritance: Changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" for Natalie Trump (Congenica) as the first option was entered by mistake.
Early onset or syndromic epilepsy v2.557 CRELD1 Ivone Leong Mode of inheritance for gene: CRELD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v1.73 ALDH1L2 Catherine Snow Classified gene: ALDH1L2 as Red List (low evidence)
Ichthyosis and erythrokeratoderma v1.73 ALDH1L2 Catherine Snow Added comment: Comment on list classification: Rating red. One individual reported with neuro-ichthyotic syndrome phenotype of congenital ichthyosis with a variant in ALDH1L2 therefore not enough evidence to ascertain gene disease relationship
Ichthyosis and erythrokeratoderma v1.73 ALDH1L2 Catherine Snow Gene: aldh1l2 has been classified as Red List (Low Evidence).
Hereditary neuropathy v1.454 SH3TC2 Arina Puzriakova Mode of inheritance for gene: SH3TC2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.453 SH3TC2 Arina Puzriakova Tag Q2_22_MOI was removed from gene: SH3TC2.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 XK Katherine Schon gene: XK was added
gene: XK was added to Early onset dementia (encompassing fronto-temporal dementia and prion disease). Sources: Literature
Mode of inheritance for gene: XK 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: XK were set to 30128557; 20301528
Phenotypes for gene: XK were set to Chorea; Dystonia; Cognitive impairment; Myopathy; Cardiomyopathy; Peripheral neuropathy; Seizures; Acanthocytosis; Compensated haemolysis
Penetrance for gene: XK were set to Complete
Review for gene: XK was set to GREEN
Added comment: McLeod syndrome causes a multi-system disorder. The presentation can resemble Huntington Disease with movement disorder, psychiatric symptoms and cognitive impairment.
Sources: Literature
Severe microcephaly v2.315 SLC38A3 Catherine Snow changed review comment from: New gene added by Konstantinos Varvagiannis. There is sufficient evidence to promote to Green at the next GMS panel update.
Gene phenotype relationship captured by OMIM, G2P and PanelApp Australia.
Marafi et al PMID: 34605855 describes 7 families accounting for 10 individuals all with ID or global DD; to: New gene added by Konstantinos Varvagiannis. There is sufficient evidence to promote to Green at the next GMS panel update.
Gene phenotype relationship captured by OMIM, G2P and PanelApp Australia.
Marafi et al PMID: 34605855 describes 7 families accounting for 10 individuals. 8/10 reported to have Microcephaly and and was more commonly postnatal and/or progressive.
Severe microcephaly v2.315 SLC38A3 Catherine Snow Entity copied from Intellectual disability v3.1650
Severe microcephaly v2.315 SLC38A3 Catherine Snow gene: SLC38A3 was added
gene: SLC38A3 was added to Severe microcephaly. Sources: Literature,Other,Expert Review Amber
Q3_22_rating tags were added to gene: SLC38A3.
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Developmental and epileptic encephalopathy 102, 619881
Penetrance for gene: SLC38A3 were set to Complete
Early onset or syndromic epilepsy v2.556 SLC38A3 Catherine Snow Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881
Early onset or syndromic epilepsy v2.555 SLC38A3 Catherine Snow Classified gene: SLC38A3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.555 SLC38A3 Catherine Snow Gene: slc38a3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.554 SLC38A3 Catherine Snow Tag Q3_22_rating tag was added to gene: SLC38A3.
Early onset or syndromic epilepsy v2.554 SLC38A3 Catherine Snow reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1650 SLC38A3 Catherine Snow Tag Q3_22_rating tag was added to gene: SLC38A3.
Intellectual disability v3.1650 SLC38A3 Catherine Snow Classified gene: SLC38A3 as Amber List (moderate evidence)
Intellectual disability v3.1650 SLC38A3 Catherine Snow Gene: slc38a3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1649 SLC38A3 Catherine Snow Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881
Intellectual disability v3.1648 SLC38A3 Catherine Snow reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.207 STT3A Tracy Lester gene: STT3A was added
gene: STT3A was added to Skeletal dysplasia. Sources: NHS GMS
Mode of inheritance for gene: STT3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STT3A were set to 34653363
Phenotypes for gene: STT3A were set to Short stature; skeletal defects; Intellectual disability; Speech delay; macrocephaly; dysmorphism
Penetrance for gene: STT3A were set to unknown
Mode of pathogenicity for gene: STT3A 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: STT3A was set to GREEN
Added comment: A recent paper has shown that heterozygous missense variants in the active site cause a disorder of glycosylation associated with short stature and skeletal defects in a majority of individuals. The gene is already green on the ID panel for AR condition but new review has been added to change to AD as well. The recessive disorder associated with this gene in primarily neurological so this inheritance model is not relevant in the context of skeletal dysplasia
Sources: NHS GMS
Intellectual disability v3.1648 STT3A Tracy Lester reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34653363; Phenotypes: short stature, skeletal defects, intellectual disability, speech delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.247 GRAP Barbara Vona gene: GRAP was added
gene: GRAP was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: GRAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRAP were set to PMID: 30610177
Phenotypes for gene: GRAP were set to Non-syndromic hearing loss
Penetrance for gene: GRAP were set to Complete
Review for gene: GRAP was set to RED
Added comment: Two consanguineous families were identified with the same c.311A>T, p.(Gln104Leu) homozygous variant in GRAP. The affected individuals in both families reported congenital profound sensorineural hearing loss. GRAP is expressed in the mouse inner ear in the neuronal fibers innervating cochlear and utricular auditory hair cells. In the fly, it is expressed in the hearing organ, called the Johnston's organ, in cells that include the mechanosensory neurons. Transgenic flies with the human variant showed loss of protein function in vivo. This gene has been assigned to the DFNB114 locus in OMIM (OMIM: #618456).
Sources: Literature
Auditory Neuropathy Spectrum Disorde v1.9 TMEM43 Barbara Vona gene: TMEM43 was added
gene: TMEM43 was added to Auditory Neuropathy Spectrum Disorder. Sources: Literature
Mode of inheritance for gene: TMEM43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM43 were set to PMID: 34050020
Phenotypes for gene: TMEM43 were set to Auditory neuropathy
Penetrance for gene: TMEM43 were set to Complete
Review for gene: TMEM43 was set to RED
Added comment: Two families with autosomal dominant inheritance patterns segregated the same p.(Arg372Ter) variant in TMEM43. Affected individuals reported late onset and progressive auditory neuropathy and were able to hear sound but not discriminate speech. Following cochlear implantation, speech discrimination was fully restored. A knock-in mouse was studied that recapitulated the progressive hearing impairment that was observed in the affected individuals. This gene has been assigned to the AUNA3 locus (OMIM: #619832).
Sources: Literature
Early onset or syndromic epilepsy v2.554 CRELD1 Natalie Trump reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32437232; Phenotypes: Developmental epileptic encephalopathy, intractable seizures, global developmental delay and cognitive delay, treatment resistant epileptic seizures, adrenal insufficiency, severe bilateral neural hearing loss, immature eye development, acute respiratory distress, submucosal cleft palate; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.554 CRELD1 Natalie Trump Deleted their review
Early onset or syndromic epilepsy v2.554 CRELD1 Natalie Trump gene: CRELD1 was added
gene: CRELD1 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: CRELD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CRELD1 were set to PMID 32437232
Phenotypes for gene: CRELD1 were set to neurodevelopmental disorder; treatment resistant epileptic seizures; mild to severe developmental and cognitive delays; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; accuse respiratory distress and submucosal cleft palate
Penetrance for gene: CRELD1 were set to Incomplete
Mode of pathogenicity for gene: CRELD1 was set to Other
Review for gene: CRELD1 was set to GREEN
gene: CRELD1 was marked as current diagnostic
Added comment: Heterozygous variants in CRELD1 are known to be associated with susceptibility to atrioventricular septal defect (AVSD), AVSD2 and AVSD associated with heterotaxy syndrome. Unaffected carriers have been reported suggesting reduced penetrance for this phenotype (OMIM 606217) .

Unpublished data has recently identified 9 unrelated families (including 3 families with 2 affected siblings each) with biallelic CRELD1 variants.

The most common features in these children with biallelic CRELD1 variants is intractable seizures. Other features include global developmental delay and cognitive delay, treatment resistant epileptic seizures, adrenal insufficiency, severe bilateral neural hearing loss, immature eye development, accute respiratory distress and submucosal cleft palate.

All identified patients to-date are compound heterozygotes and each have one missense variant and one frameshift variant.
A recurrent missense variant (p.Cys192Tyr) has been identified in 8 individuals from 5 unrelated families. This missense change has been reported as a compound heterozygote with a frameshift variant a patient with seizures and global developmental delay (PMID: 32437232). This variant affects a cysteine residue that is predicted to form a disulphide bond in the protein which is important for protein folding and structural stability.
Two recurrent frameshift variants have also been identified:
- The p.Gln320ArgfsTer25 variant was found in 3 unrelated individuals (reported as compound heterozyogote in PMID: 32437232).
- The p.Ala377ThrfsTer7 variant was found in 5 individuals from 3 unrelated families.

CRELD1 encodes a member of a subfamily of epidermal growth factor-related proteins. CRELD1 plays a pivitol role in heart development and has also been shown to be an important gatekeeper of immune system homeostasis (PMID: 33169013).

There is one publication that reports a patient with seizures and global developmental delay with biallelic variants in CRELD1 (PMID: 32437232) but no other association between CRELD1 and brain function has been reported to date. Significantly, CRELD1 has high expression in human brain across different developmental stages.

There is no phenotype associated with biallelic CRELD1 variants in OMIM or G2P.
Sources: Expert Review
Undiagnosed metabolic disorders v1.542 APOB Arina Puzriakova Mode of inheritance for gene: APOB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.541 APOB Arina Puzriakova Tag Q4_21_MOI was removed from gene: APOB.
Severe hypertriglyceridaemia v1.17 APOA5 Arina Puzriakova Mode of inheritance for gene: APOA5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Severe hypertriglyceridaemia v1.16 APOA5 Arina Puzriakova Tag Q3_21_MOI was removed from gene: APOA5.
Undiagnosed metabolic disorders v1.541 APOA5 Arina Puzriakova Mode of inheritance for gene: APOA5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.540 APOA5 Arina Puzriakova Tag Q3_21_MOI was removed from gene: APOA5.
Hereditary neuropathy or pain disorder v1.103 KIF1A Arina Puzriakova Tag Q3_21_expert_review was removed from gene: KIF1A.
Undiagnosed metabolic disorders v1.540 ALDH18A1 Arina Puzriakova Mode of inheritance for gene: ALDH18A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.539 ALDH18A1 Arina Puzriakova Tag Q3_21_MOI was removed from gene: ALDH18A1.
DDG2P v2.76 CLTC Eleanor Williams commented on gene: CLTC
Nephrocalcinosis or nephrolithiasis v2.36 SLC34A3 Eleanor Williams Tag Q3_22_MOI tag was added to gene: SLC34A3.
Tag Q3_22_NHS_review tag was added to gene: SLC34A3.
Nephrocalcinosis or nephrolithiasis v2.36 SLC34A3 Eleanor Williams Phenotypes for gene: SLC34A3 were changed from Hypophosphatemic rickets with hypercalciuria, 241530; HHRH; recent publication added nephrolithiasis. to Hypophosphatemic rickets with hypercalciuria, OMIM:241530; HHRH; hereditary hypophosphatemic rickets with hypercalciuria, MONDO:0009431
Nephrocalcinosis or nephrolithiasis v2.35 SLC34A3 Eleanor Williams Publications for gene: SLC34A3 were set to 25296721; 26543054; 24924704; 24700880
Nephrocalcinosis or nephrolithiasis v2.34 SLC34A3 Eleanor Williams Publications for gene: SLC34A3 were set to PMID: 25296721; 26543054; 24924704; 24700880
Nephrocalcinosis or nephrolithiasis v2.33 SLC34A3 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving MOI as Biallelic for now but with recommendation for change to BOTH mono and bi-allelic at the next GMS review.
Nephrocalcinosis or nephrolithiasis v2.33 SLC34A3 Eleanor Williams Mode of inheritance for gene: SLC34A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v1.27 RRAGD Eleanor Williams commented on gene: RRAGD: Copied this gene from the Renal tubulopathies panel. In 6 cases reported in PMID: 34607910 (Schlingmann et al 2021) the probands also had dilated cardiomyopathy. Abstract only accessed.
Dilated and arrhythmogenic cardiomyopathy v1.27 RRAGD Eleanor Williams Entity copied from Renal tubulopathies v2.62
Dilated and arrhythmogenic cardiomyopathy v1.27 RRAGD Eleanor Williams gene: RRAGD was added
gene: RRAGD was added to Dilated cardiomyopathy - adult and teen. Sources: Expert Review Amber,Literature
Q3_22_rating, Q3_22_NHS_review tags were added to gene: RRAGD.
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to hypomagnesaemia; cardiomyopathy; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130
Penetrance for gene: RRAGD were set to Complete
Mode of pathogenicity for gene: RRAGD was set to Other
Renal tubulopathies v2.62 RRAGD Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype.

As reviewer states PMID: 34607910 (Schlingmann et al 2021) reports 8 cases where patients with hypomagnesaemia were found to have heterozygous (mostly de novo) missense variants in RRAGD. 6 patients also had dilated cardiomyopathy. In addition they report a family with a heterozygous variant in RRAGD that segregated with a kidney phenotype in eight members.; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

As reviewer states PMID: 34607910 (Schlingmann et al 2021) reports 8 cases where patients with hypomagnesaemia were found to have heterozygous (mostly de novo) missense variants in RRAGD. 6 patients also had dilated cardiomyopathy. In addition they report a family with a heterozygous variant in RRAGD that segregated with a kidney phenotype in eight members. Abstract only accessed.
Renal tubulopathies v2.62 RRAGD Eleanor Williams Classified gene: RRAGD as Amber List (moderate evidence)
Renal tubulopathies v2.62 RRAGD Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for GREEN rating following GMS review.
Renal tubulopathies v2.62 RRAGD Eleanor Williams Gene: rragd has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.61 RRAGD Eleanor Williams commented on gene: RRAGD
Renal tubulopathies v2.61 RRAGD Eleanor Williams Phenotypes for gene: RRAGD were changed from hypomagnesaemia; cardiomyopathy to hypomagnesaemia; cardiomyopathy; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130
Renal tubulopathies v2.60 RRAGD Eleanor Williams Publications for gene: RRAGD were set to PMID: 34607910
Renal tubulopathies v2.59 RRAGD Eleanor Williams Tag Q3_22_rating tag was added to gene: RRAGD.
Tag Q3_22_NHS_review tag was added to gene: RRAGD.
Intellectual disability v3.1648 CNNM2 Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Early onset or syndromic epilepsy v2.554 CNNM2 Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Renal tubulopathies v2.59 CNNM2 Eleanor Williams Classified gene: CNNM2 as Amber List (moderate evidence)
Renal tubulopathies v2.59 CNNM2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation of GREEN rating following GMS review. Many monoallelic cases reported plus 2 biallelic.
Renal tubulopathies v2.59 CNNM2 Eleanor Williams Gene: cnnm2 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.58 CNNM2 Eleanor Williams Tag Q3_22_rating tag was added to gene: CNNM2.
Tag Q3_22_MOI tag was added to gene: CNNM2.
Tag Q3_22_NHS_review tag was added to gene: CNNM2.
Renal tubulopathies v2.58 CNNM2 Eleanor Williams Phenotypes for gene: CNNM2 were changed from hypomagnesaemia; seizures; intellectual disability to Hypomagnesemia 6, renal, OMIM:613882; Hypomagnesemia, seizures, and mental retardation, OMIM:616418; renal hypomagnesemia 6, MONDO:0013480; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Renal tubulopathies v2.57 CNNM2 Eleanor Williams Publications for gene: CNNM2 were set to PMID: 33600043; 30026055; 32997713; 34604137; 33859252; 24699222; 35002148; 21397062
Renal tubulopathies v2.56 CNNM2 Eleanor Williams Added comment: Comment on mode of pathogenicity: There is a mix of missense and truncating variants reported.
Renal tubulopathies v2.56 CNNM2 Eleanor Williams Mode of pathogenicity for gene: CNNM2 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Renal tubulopathies v2.55 CNNM2 Eleanor Williams Mode of inheritance for gene: CNNM2 was changed from Other to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Renal tubulopathies v2.54 CNNM2 Eleanor Williams reviewed gene: CNNM2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 6, renal, OMIM:613882, Hypomagnesemia, seizures, and mental retardation, OMIM:616418, renal hypomagnesemia 6, MONDO:0013480; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.553 ATP2B1 Catherine Snow Phenotypes for gene: ATP2B1 were changed from Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck to Intellectual developmental disorder, autosomal dominant 66, 619910
Early onset or syndromic epilepsy v2.552 ATP2B1 Catherine Snow Classified gene: ATP2B1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.552 ATP2B1 Catherine Snow Gene: atp2b1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.551 ATP2B1 Catherine Snow Tag watchlist tag was added to gene: ATP2B1.
Early onset or syndromic epilepsy v2.551 ATP2B1 Catherine Snow reviewed gene: ATP2B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1647 ATP2B1 Catherine Snow Phenotypes for gene: ATP2B1 were changed from Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck to Intellectual developmental disorder, autosomal dominant 66, 619910
Intellectual disability v3.1646 ATP2B1 Catherine Snow Classified gene: ATP2B1 as Amber List (moderate evidence)
Intellectual disability v3.1646 ATP2B1 Catherine Snow Gene: atp2b1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1645 ATP2B1 Catherine Snow Tag Q3_22_rating tag was added to gene: ATP2B1.
Intellectual disability v3.1645 ATP2B1 Catherine Snow reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.551 ADD1 Catherine Snow Tag watchlist tag was added to gene: ADD1.
Early onset or syndromic epilepsy v2.551 ADD1 Catherine Snow Classified gene: ADD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.551 ADD1 Catherine Snow Gene: add1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.550 ADD1 Catherine Snow reviewed gene: ADD1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Amyotrophic lateral sclerosis/motor neuron disease v1.60 SETX Arina Puzriakova Mode of inheritance for gene: SETX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amyotrophic lateral sclerosis/motor neuron disease v1.59 SETX Arina Puzriakova Tag Q2_22_MOI was removed from gene: SETX.
Intellectual disability v3.1645 ADD1 Catherine Snow Classified gene: ADD1 as Amber List (moderate evidence)
Intellectual disability v3.1645 ADD1 Catherine Snow Gene: add1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1645 ADD1 Catherine Snow Classified gene: ADD1 as Amber List (moderate evidence)
Intellectual disability v3.1645 ADD1 Catherine Snow Gene: add1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1644 ADD1 Catherine Snow Tag Q3_22_rating tag was added to gene: ADD1.
Intellectual disability v3.1644 ADD1 Catherine Snow commented on gene: ADD1
Fetal anomalies v1.880 NDUFB11 Rhiannon Mellis reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25772934; Phenotypes: Linear skin defects, cardiomyopathy, ACC; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v1.880 TMEM70 Rhiannon Mellis reviewed gene: TMEM70: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21147908, PMID: 24740313, PMID: 26550569, PMID: 20335238, PMID: 25326274; Phenotypes: IUGR, Oligohydramnios, Anhydramnios, Cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.880 SPTA1 Rhiannon Mellis gene: SPTA1 was added
gene: SPTA1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: SPTA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SPTA1 were set to PMID: 34132406; PMID: 31333484
Phenotypes for gene: SPTA1 were set to Hydrops fetalis; Congenital anaemia
Review for gene: SPTA1 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH).

Outcome of review: Likely that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as an Amber gene, pending further evidence and review of other congenital anaemia genes that may cause hydrops.

Currently rated Green on the following other PanelApp panel(s): Congenital anaemias

Details of review: The fetal case in Wagner et al 2021 (PMID: 34132406) had hydrops secondary to severe fetal anaemia at 28/40. Chonat et al 2019 (PMID: 31333484) also report 3 further unrelated cases with hydrops/fetal anaemia.
Sources: Literature, Expert Review
Fetal anomalies v1.880 PLOD3 Rhiannon Mellis gene: PLOD3 was added
gene: PLOD3 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD3 were set to PMID: 18834968; PMID: 33743358
Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency; IUGR; Contractures
Review for gene: PLOD3 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH).

Outcome of review: May be fetally relevant, support adding to the Fetal anomalies panel as an Amber gene, pending more evidence.

Rated Green on the following other PanelApp panel(s): Cataracts

Details of review: Phenotype on OMIM includes potentially fetally detectable phenotypes: IUGR, contractures, cataracts (?whether congenital). Salo et al 2008 (PMID: 18834968) describes a proband with IUGR, flat facial profile, simple, low-set ears, shallow orbits, short, upturned nose, and downturned corners of the mouth. Skeletal features included talipes equinovarus, progressive scoliosis, osteopenia, and several pathologic fractures. A sib had IUGR and was stillborn, with finger contractures (but didn't seem to have molecular testing?).

The fetal case in Cao et al 2021 had NT 5.2 mm (12/40), Reduced fetal movement (12/40), FGR (24/40), Enlarged posterior fossa (24/40), Intracranial haemorrhage (24/40), Clenched hands and fixated extended knees (24/40).
Sources: Literature, Expert Review
Fetal anomalies v1.880 PLD1 Rhiannon Mellis reviewed gene: PLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33142350; Phenotypes: Cardiomyopathy, Congenital heart malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.880 NMNAT2 Rhiannon Mellis reviewed gene: NMNAT2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33442022; Phenotypes: Hydrops fetalis, brain malformation, oligohydramnios; Mode of inheritance: None
Fetal anomalies v1.880 NEXN Rhiannon Mellis gene: NEXN was added
gene: NEXN was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: NEXN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEXN were set to PMID: 32058062; PMID: 33027564
Phenotypes for gene: NEXN were set to Cardiomyopathy
Review for gene: NEXN was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH).

Outcome of review: Gene usually causes adult-onset AD cardiomyopathy. However, there may be a fetally relevant phenotype with biallelic variants. Support adding to the Fetal anomalies panel as an Amber gene, pending more evidence of fetal phenotype (only 2 reported unrelated cases to date).

Currently rated Green on the following other PanelApp panel(s): Cardiomyopathy (dilated)

Details of review: The fetal case in Sparks et al (PMID: 33027564) had pericardial effusion, ascites, cardiomegaly, dilation and hypertrophy of cardiac ventricles, hypoplastic and dysplastic aortic valve, diminished systolic function, fetal growth restriction, and was stillborn. 2 NEXN variants found in the fetus (1 mat inherited, 1 de novo) but unable to confirm phase.
The fetal case in Rinaldi et al 2021 (PMID: 32058062) had Cardiomegaly, low contractility/outflow, fibroelastosis of right ventricle. The fetus was compound het for NEXN variants and parents were both unaffected het with normal echos. They'd had one previous pregnancy with same phenotype.
Sources: Literature, Expert Review
Fetal anomalies v1.880 MED13L Rhiannon Mellis reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33142350, PMID: 32058062; Phenotypes: Intellectual disability, dysmorphic features, congenital heart malformations, talipes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.550 OGDHL Arina Puzriakova Entity copied from Intellectual disability v3.1644
Early onset or syndromic epilepsy v2.550 OGDHL Arina Puzriakova gene: OGDHL was added
gene: OGDHL was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: OGDHL.
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Monogenic hearing loss v2.247 OGDHL Arina Puzriakova Entity copied from Intellectual disability v3.1644
Monogenic hearing loss v2.247 OGDHL Arina Puzriakova gene: OGDHL was added
gene: OGDHL was added to Hearing loss. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: OGDHL.
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Ataxia and cerebellar anomalies - childhood onset v2.300 OGDHL Arina Puzriakova Entity copied from Intellectual disability v3.1644
Ataxia and cerebellar anomalies - childhood onset v2.300 OGDHL Arina Puzriakova gene: OGDHL was added
gene: OGDHL was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: OGDHL.
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Intellectual disability v3.1644 OGDHL Arina Puzriakova Tag Q3_22_rating tag was added to gene: OGDHL.
Intellectual disability v3.1644 OGDHL Arina Puzriakova Phenotypes for gene: OGDHL were changed from Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Intellectual disability v3.1643 OGDHL Arina Puzriakova Classified gene: OGDHL as Amber List (moderate evidence)
Intellectual disability v3.1643 OGDHL Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'moderate' disease confidence rating in G2P for 'OGDHL-related neurodevelopmental disorder with seizures, hearing loss and gait ataxia'.

At least 10 individuals from 9 unrelated families identified with biallelic variants in this gene (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).
Intellectual disability v3.1643 OGDHL Arina Puzriakova Gene: ogdhl has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1642 OGDHL Arina Puzriakova Publications for gene: OGDHL were set to 34800363
Hereditary spastic paraplegia, childhood onset v2.140 NSRP1 Arina Puzriakova Entity copied from Intellectual disability v3.1641
Hereditary spastic paraplegia, childhood onset v2.140 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Malformations of cortical development v2.148 NSRP1 Arina Puzriakova Entity copied from Intellectual disability v3.1641
Malformations of cortical development v2.148 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Malformations of cortical development. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Severe microcephaly v2.314 NSRP1 Arina Puzriakova Entity copied from Intellectual disability v3.1641
Severe microcephaly v2.314 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Early onset or syndromic epilepsy v2.549 NSRP1 Arina Puzriakova Entity copied from Intellectual disability v3.1641
Early onset or syndromic epilepsy v2.549 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSRP1.
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Classified gene: NSRP1 as Amber List (moderate evidence)
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'strong' disease confidence rating in G2P for 'NSRP1-associated developmental delay, epilepsy and microcephaly'.

Six individuals from three families with different homozygous LoF NSRP1 variants identified by Calame et al. 2021 (PMID: 34385670). Main clinical features include ID/DD (6/6), epilepsy (6/6, drug-resistant in 3/6), hypotonia (6/6), appendicular spasticity (6/6), microcephaly (5/6, Z-scores −0.95 to −5.60). Brain abnormalities included under-opercularization (3/4), simplified gyral pattern (3/4), superior and/or inferior cerebellar vermian hypoplasia (3/4), corpus callosum dysgenesis (1/4), and thin brainstem (1/4).
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Gene: nsrp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1640 NSRP1 Arina Puzriakova Phenotypes for gene: NSRP1 were changed from Epilepsy; Cerebral palsy; microcephaly; Intellectual disability to NSRP1-associated developmental delay, epilepsy and microcephaly
Severe microcephaly v2.313 HMGB1 Arina Puzriakova Entity copied from Intellectual disability v3.1639
Severe microcephaly v2.313 HMGB1 Arina Puzriakova gene: HMGB1 was added
gene: HMGB1 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: HMGB1.
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to 34164801
Phenotypes for gene: HMGB1 were set to Developmental delay and microcephaly
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Classified gene: HMGB1 as Amber List (moderate evidence)
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update on ID and microcephaly gene panel based on >3 unrelated cases presenting with relevant phenotype due to heterozygous variant in the HMGB1 gene (PMID: 34164801)
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Gene: hmgb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1638 HMGB1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: HMGB1.
Proteinuric renal disease v2.77 GLA Eleanor Williams Classified gene: GLA as Amber List (moderate evidence)
Proteinuric renal disease v2.77 GLA Eleanor Williams Added comment: Comment on list classification: Following review by an NHS expert, this gene is recommended to be rated as Green following GMS review.
Proteinuric renal disease v2.77 GLA Eleanor Williams Gene: gla has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.76 GLA Eleanor Williams Tag Q3_22_rating tag was added to gene: GLA.
Tag Q3_22_NHS_review tag was added to gene: GLA.
Leukodystrophy, adult onset v1.43 GLA Eleanor Williams Tag Q3_22_expert_review was removed from gene: GLA.
Leukodystrophy, adult onset v1.43 GLA Eleanor Williams changed review comment from: Comment on mode of inheritance: The mode of inheritance for this gene should be considered for change to 'X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' which would make it in line with all other GMS panels.

Wang et al 2007 (PMID: 17224688) reports the phenotypes of 44 females with GLA variants. Only 1 was considered asymptomatic. 31/41 were ascertained following diagnosis of another affected family member. 24% (9/37) reported symptoms of TIA (transient ischemic attacks) and 22% (8/36) had sustained at least one CVA (cerebrovascular accidents). They report that 7 patients had both TIA and CVA and that the prevalence of CVA in this cohort (22%) was nearly ten times higher than the prevalence in the United States (2.3% of all women older than 18 years). They say that heterozygous Fabry women should not be called carriers due to the serious nature of their symptoms.; to: Comment on mode of inheritance: The mode of inheritance for this gene should be considered for change to 'X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' which would make it in line with all other GMS panels.

Wang et al 2007 (PMID: 17224688) reports the phenotypes of 44 females with GLA variants. Only 1 was considered asymptomatic. 31/41 were ascertained following diagnosis of another affected family member. 24% (9/37) reported symptoms of TIA (transient ischemic attacks) and 22% (8/36) had sustained at least one CVA (cerebrovascular accidents). They report that 7 patients had both TIA and CVA and that the prevalence of CVA in this cohort (22%) was nearly ten times higher than the prevalence in the United States (2.3% of all women older than 18 years). They say that heterozygous Fabry women should not be called carriers due to the serious nature of their symptoms.
Leukodystrophy, adult onset v1.43 GLA Eleanor Williams Added comment: Comment on mode of inheritance: The mode of inheritance for this gene should be considered for change to 'X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' which would make it in line with all other GMS panels.

Wang et al 2007 (PMID: 17224688) reports the phenotypes of 44 females with GLA variants. Only 1 was considered asymptomatic. 31/41 were ascertained following diagnosis of another affected family member. 24% (9/37) reported symptoms of TIA (transient ischemic attacks) and 22% (8/36) had sustained at least one CVA (cerebrovascular accidents). They report that 7 patients had both TIA and CVA and that the prevalence of CVA in this cohort (22%) was nearly ten times higher than the prevalence in the United States (2.3% of all women older than 18 years). They say that heterozygous Fabry women should not be called carriers due to the serious nature of their symptoms.
Leukodystrophy, adult onset v1.43 GLA Eleanor Williams Mode of inheritance for gene: GLA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Leukodystrophy, adult onset v1.42 GLA Eleanor Williams Tag Q3_22_MOI tag was added to gene: GLA.
Tag Q3_22_expert_review tag was added to gene: GLA.
Cystic kidney disease v2.53 GLA Eleanor Williams Added comment: Comment on mode of inheritance: There is evidence that heterozyous females are not always asymptomatic carriers, with renal disease being reported as part of the phenotype in several cases (PMID: 17224688 Wang et al 2007, PMID: 29770213 McCloskey et al 2018).
Cystic kidney disease v2.53 GLA Eleanor Williams Mode of inheritance for gene: GLA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Cystic kidney disease v2.52 GLA Eleanor Williams Phenotypes for gene: GLA were changed from to Fabry disease, OMIM:301500; Fabry disease, MONDO:0010526; Renal cyst, HP:0000107; renal parapelvic cysts
Cystic kidney disease v2.51 GLA Eleanor Williams Publications for gene: GLA were set to
Cystic kidney disease v2.50 GLA Eleanor Williams Classified gene: GLA as Amber List (moderate evidence)
Cystic kidney disease v2.50 GLA Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for a green rating following GMS review. More than 3 cases reported with renal parapelvic cysts.
Cystic kidney disease v2.50 GLA Eleanor Williams Gene: gla has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.49 GLA Eleanor Williams Tag Q3_22_rating tag was added to gene: GLA.
Tag Q3_22_NHS_review tag was added to gene: GLA.
Cystic kidney disease v2.49 GLA Eleanor Williams commented on gene: GLA
Cystic kidney disease v2.49 PAX2 Eleanor Williams changed review comment from: As reviewer notes PAX2 is associated with Papillorenal syndrome #120330 (AD) in OMIM and Renal cysts and Multicystic dysplastic kidneys are listed as clinical features.

In PMID: 22213154 Bowers et al 2012 review of PAX2 variants found in patients with renal coloboma syndrome they note that renal cysts were found in 8% of patients (n = 13), and multicystic dysplastic kidneys in 6% (n = 7) from more than three unrelated families.

Deng et al 2019 - PMID: 31060108 examined the phenotypes of 10 children (one was Mongolian and the rest were of Han Chinese ethnicity) with PAX2 variants. Renal cysts were detected in five patients.; to: As reviewer notes PAX2 is associated with Papillorenal syndrome #120330 (AD) in OMIM and Renal cysts and Multicystic dysplastic kidneys are listed as clinical features.

In PMID: 22213154 Bowers et al 2012 review of PAX2 variants found in patients with renal coloboma syndrome they note that renal cysts were found in 8% of patients (n = 13), and multicystic dysplastic kidneys in 6% (n = 7) from more than three unrelated families.

Deng et al 2019 - PMID: 31060108 examined the phenotypes of 10 children (one was Mongolian and the rest were of Han Chinese ethnicity) with PAX2 variants. Renal cysts were detected in five patients.

A further case of cystic renal disease in a patient with PAX2 variants are reported in PMID: 22213154
Cystic kidney disease v2.49 PAX2 Eleanor Williams Publications for gene: PAX2 were set to PMID: 33746522; 16049068; 22213154
Cystic kidney disease v2.48 PAX2 Eleanor Williams Phenotypes for gene: PAX2 were changed from cystic renal disease to Papillorenal syndrome, OMIM:120330; renal coloboma syndrome, MONDO:0007352
Cystic kidney disease v2.47 PAX2 Eleanor Williams Mode of inheritance for gene: PAX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.46 PAX2 Eleanor Williams Classified gene: PAX2 as Amber List (moderate evidence)
Cystic kidney disease v2.46 PAX2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation for green rating following GMS review. There are more than 3 cases reported where renal cysts are part of the phenotype.
Cystic kidney disease v2.46 PAX2 Eleanor Williams Gene: pax2 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.45 PAX2 Eleanor Williams Tag Q3_22_rating tag was added to gene: PAX2.
Tag Q3_22_NHS_review tag was added to gene: PAX2.
Cystic kidney disease v2.45 PAX2 Eleanor Williams reviewed gene: PAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22213154, 31060108; Phenotypes: Papillorenal syndrome, OMIM:120330, renal coloboma syndrome, MONDO:0007352; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mitochondrial disorders v2.116 COX16 Arina Puzriakova Tag watchlist tag was added to gene: COX16.
Possible mitochondrial disorder, nuclear genes v1.93 COX16 Arina Puzriakova reviewed gene: COX16: Rating: ; Mode of pathogenicity: None; Publications: 33169484; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 22, OMIM:619355; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.16 COX16 Arina Puzriakova reviewed gene: COX16: Rating: ; Mode of pathogenicity: None; Publications: 33169484; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 22, OMIM:619355; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.116 COX16 Arina Puzriakova Classified gene: COX16 as Amber List (moderate evidence)
Mitochondrial disorders v2.116 COX16 Arina Puzriakova Added comment: Comment on list classification: Rating Amber on the basis of two unrelated cases reported in literature (PMID: 33169484), although notably both harbour the same homozygous variant. Further cases would help corroborate this gene-disease association (added 'watchlist' tag)
Mitochondrial disorders v2.116 COX16 Arina Puzriakova Gene: cox16 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder, nuclear genes v1.93 COX16 Arina Puzriakova Mode of inheritance for gene: COX16 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.16 COX16 Arina Puzriakova Mode of inheritance for gene: COX16 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.115 COX16 Arina Puzriakova Publications for gene: COX16 were set to
Possible mitochondrial disorder, nuclear genes v1.92 COX16 Arina Puzriakova Publications for gene: COX16 were set to
Mitochondrial disorder with complex IV deficiency v1.15 COX16 Arina Puzriakova Publications for gene: COX16 were set to
Possible mitochondrial disorder, nuclear genes v1.91 COX16 Arina Puzriakova Phenotypes for gene: COX16 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 22, OMIM:619355; Hypertrophic cardiomyopathy; Encephalopathy; Severe fatal lactic acidosis
Mitochondrial disorder with complex IV deficiency v1.14 COX16 Arina Puzriakova Phenotypes for gene: COX16 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 22, OMIM:619355; Hypertrophic cardiomyopathy; Encephalopathy; Severe fatal lactic acidosis
Mitochondrial disorders v2.114 COX16 Arina Puzriakova Phenotypes for gene: COX16 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 22, OMIM:619355; Hypertrophic cardiomyopathy; Encephalopathy; Severe fatal lactic acidosis
Mitochondrial disorders v2.113 COX16 Arina Puzriakova Mode of inheritance for gene: COX16 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1638 POLRMT Arina Puzriakova Entity copied from Mitochondrial disorders v2.112
Intellectual disability v3.1638 POLRMT Arina Puzriakova gene: POLRMT was added
gene: POLRMT was added to Intellectual disability. Sources: NHS GMS,Expert Review Amber
Q3_22_rating tags were added to gene: POLRMT.
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 24386581; 33602924
Phenotypes for gene: POLRMT were set to Combined oxidative phosphorylation deficiency 55, OMIM:619743
Possible mitochondrial disorder, nuclear genes v1.90 POLRMT Arina Puzriakova Tag Q3_22_rating tag was added to gene: POLRMT.
Possible mitochondrial disorder, nuclear genes v1.90 POLRMT Arina Puzriakova Classified gene: POLRMT as Amber List (moderate evidence)
Possible mitochondrial disorder, nuclear genes v1.90 POLRMT Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update.

POLRMT is associated with a relevant phenotype in OMIM (MIM# 619743). At least 8 individuals from 7 unrelated families reported in literature (PMID: 33602924) with distinct variant in this gene (5 biallelic, 2 monoallelic) associated with mitochondrial dysfunction and a broad spectrum of neurological presentations. Affected individuals presented with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.
Possible mitochondrial disorder, nuclear genes v1.90 POLRMT Arina Puzriakova Gene: polrmt has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.112 POLRMT Arina Puzriakova Tag Q3_22_rating tag was added to gene: POLRMT.
Mitochondrial disorders v2.112 POLRMT Arina Puzriakova Classified gene: POLRMT as Amber List (moderate evidence)
Mitochondrial disorders v2.112 POLRMT Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update.

POLRMT is associated with a relevant phenotype in OMIM (MIM# 619743). At least 7 unrelated families reported in literature (PMID: 33602924) with distinct variant in this gene associated with mitochondrial dysfunction and a broad spectrum of neurological presentations.
Mitochondrial disorders v2.112 POLRMT Arina Puzriakova Gene: polrmt has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.111 POLRMT Arina Puzriakova Publications for gene: POLRMT were set to
Possible mitochondrial disorder, nuclear genes v1.89 POLRMT Arina Puzriakova Phenotypes for gene: POLRMT were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 55, OMIM:619743
Possible mitochondrial disorder, nuclear genes v1.88 POLRMT Arina Puzriakova Publications for gene: POLRMT were set to
Mitochondrial disorders v2.110 POLRMT Arina Puzriakova Phenotypes for gene: POLRMT were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 55, OMIM:619743
Fetal anomalies v1.880 LRIT3 Arina Puzriakova commented on gene: LRIT3
Intellectual disability v3.1637 GJB2 Arina Puzriakova commented on gene: GJB2
Congenital myopathy v2.88 CASQ1 Arina Puzriakova commented on gene: CASQ1
Congenital muscular dystrophy v2.30 DPM3 Arina Puzriakova commented on gene: DPM3
Mitochondrial disorders v2.109 UQCR11 Arina Puzriakova commented on gene: UQCR11
Mitochondrial disorders v2.109 UQCR10 Arina Puzriakova commented on gene: UQCR10
Mitochondrial disorders v2.109 UQCC1 Arina Puzriakova commented on gene: UQCC1
Mitochondrial disorders v2.109 SDHAF4 Arina Puzriakova commented on gene: SDHAF4
Mitochondrial disorders v2.109 SDHAF3 Arina Puzriakova commented on gene: SDHAF3
Mitochondrial disorders v2.109 NDUFAF7 Arina Puzriakova commented on gene: NDUFAF7
Mitochondrial disorders v2.109 GATC Arina Puzriakova commented on gene: GATC
Mitochondrial disorders v2.109 GATB Arina Puzriakova commented on gene: GATB
Mitochondrial disorders v2.109 G6PC Arina Puzriakova commented on gene: G6PC
Mitochondrial disorders v2.109 ERAL1 Arina Puzriakova commented on gene: ERAL1
Mitochondrial disorders v2.109 COX6B2 Arina Puzriakova commented on gene: COX6B2
Mitochondrial disorders v2.109 COX19 Arina Puzriakova commented on gene: COX19
Mitochondrial disorders v2.109 COX18 Arina Puzriakova commented on gene: COX18
Mitochondrial disorders v2.109 COX17 Arina Puzriakova commented on gene: COX17
Mitochondrial disorders v2.109 COX11 Arina Puzriakova commented on gene: COX11
Mitochondrial disorders v2.109 COQ5 Arina Puzriakova commented on gene: COQ5
Mitochondrial disorders v2.109 COA4 Arina Puzriakova commented on gene: COA4
Mitochondrial disorders v2.109 COA3 Arina Puzriakova commented on gene: COA3
Mitochondrial disorders v2.109 ATPAF1 Arina Puzriakova commented on gene: ATPAF1
Mitochondrial disorders v2.109 ATP5L2 Arina Puzriakova commented on gene: ATP5L2
Mitochondrial disorders v2.109 ATP5L Arina Puzriakova commented on gene: ATP5L
Mitochondrial disorders v2.109 ATP5H Arina Puzriakova commented on gene: ATP5H
Mitochondrial disorders v2.109 ATP5F1 Arina Puzriakova commented on gene: ATP5F1
Iron metabolism disorders - NOT common HFE mutations v1.35 HEPH Arina Puzriakova commented on gene: HEPH
Iron metabolism disorders - NOT common HFE mutations v1.35 FTH1 Arina Puzriakova commented on gene: FTH1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.572 PMS2 Arina Puzriakova commented on gene: PMS2
Primary immunodeficiency or monogenic inflammatory bowel disease v2.572 CFHR5 Arina Puzriakova commented on gene: CFHR5
Primary immunodeficiency or monogenic inflammatory bowel disease v2.572 CFHR4 Arina Puzriakova commented on gene: CFHR4
Primary immunodeficiency or monogenic inflammatory bowel disease v2.572 CFHR3 Arina Puzriakova commented on gene: CFHR3
Primary immunodeficiency or monogenic inflammatory bowel disease v2.572 CFHR1 Arina Puzriakova commented on gene: CFHR1
Palmoplantar keratodermas v1.18 STK11 Arina Puzriakova commented on gene: STK11
Epidermolysis bullosa and congenital skin fragility v1.53 EGFR Arina Puzriakova commented on gene: EGFR
Epidermolysis bullosa and congenital skin fragility v1.53 DSG3 Arina Puzriakova commented on gene: DSG3
Possible mitochondrial disorder, nuclear genes v1.87 ATP5F1 Arina Puzriakova Classified gene: ATP5F1 as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.87 ATP5F1 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.87 ATP5F1 Arina Puzriakova Gene: atp5f1 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex V deficiency v1.7 ATP5F1 Arina Puzriakova Classified gene: ATP5F1 as Red List (low evidence)
Mitochondrial disorder with complex V deficiency v1.7 ATP5F1 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex V deficiency v1.7 ATP5F1 Arina Puzriakova Gene: atp5f1 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder, nuclear genes v1.86 ATP5H Arina Puzriakova Classified gene: ATP5H as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.86 ATP5H Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.86 ATP5H Arina Puzriakova Gene: atp5h has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex V deficiency v1.6 ATP5H Arina Puzriakova Classified gene: ATP5H as Red List (low evidence)
Mitochondrial disorder with complex V deficiency v1.6 ATP5H Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex V deficiency v1.6 ATP5H Arina Puzriakova Gene: atp5h has been classified as Red List (Low Evidence).
Possible mitochondrial disorder, nuclear genes v1.85 ATP5L Arina Puzriakova Classified gene: ATP5L as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.85 ATP5L Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.85 ATP5L Arina Puzriakova Gene: atp5l has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex V deficiency v1.5 ATP5L Arina Puzriakova Classified gene: ATP5L as Red List (low evidence)
Mitochondrial disorder with complex V deficiency v1.5 ATP5L Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex V deficiency v1.5 ATP5L Arina Puzriakova Gene: atp5l has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex V deficiency v1.4 ATP5L2 Arina Puzriakova Classified gene: ATP5L2 as Red List (low evidence)
Mitochondrial disorder with complex V deficiency v1.4 ATP5L2 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex V deficiency v1.4 ATP5L2 Arina Puzriakova Gene: atp5l2 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder, nuclear genes v1.84 ATP5L2 Arina Puzriakova Classified gene: ATP5L2 as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.84 ATP5L2 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.84 ATP5L2 Arina Puzriakova Gene: atp5l2 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder, nuclear genes v1.83 UQCR10 Arina Puzriakova Classified gene: UQCR10 as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.83 UQCR10 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.83 UQCR10 Arina Puzriakova Gene: uqcr10 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex III deficiency v1.6 UQCR10 Arina Puzriakova Classified gene: UQCR10 as Red List (low evidence)
Mitochondrial disorder with complex III deficiency v1.6 UQCR10 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex III deficiency v1.6 UQCR10 Arina Puzriakova Gene: uqcr10 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex III deficiency v1.5 UQCC1 Arina Puzriakova Classified gene: UQCC1 as Red List (low evidence)
Mitochondrial disorder with complex III deficiency v1.5 UQCC1 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex III deficiency v1.5 UQCC1 Arina Puzriakova Gene: uqcc1 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder, nuclear genes v1.82 UQCC1 Arina Puzriakova Classified gene: UQCC1 as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.82 UQCC1 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.82 UQCC1 Arina Puzriakova Gene: uqcc1 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder, nuclear genes v1.81 UQCR11 Arina Puzriakova Classified gene: UQCR11 as Red List (low evidence)
Possible mitochondrial disorder, nuclear genes v1.81 UQCR11 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Possible mitochondrial disorder, nuclear genes v1.81 UQCR11 Arina Puzriakova Gene: uqcr11 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex III deficiency v1.4 UQCR11 Arina Puzriakova Classified gene: UQCR11 as Red List (low evidence)
Mitochondrial disorder with complex III deficiency v1.4 UQCR11 Arina Puzriakova Added comment: Comment on list classification: Demoting to Red as there is no evidence for Mendelian gene-disease association at this time
Mitochondrial disorder with complex III deficiency v1.4 UQCR11 Arina Puzriakova Gene: uqcr11 has been classified as Red List (Low Evidence).
Severe microcephaly v2.312 GINS3 Ivone Leong Tag Q3_22_rating tag was added to gene: GINS3.
Severe microcephaly v2.312 GINS3 Ivone Leong Classified gene: GINS3 as Amber List (moderate evidence)
Severe microcephaly v2.312 GINS3 Ivone Leong Gene: gins3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.311 GINS3 Ivone Leong Entity copied from Growth failure in early childhood v1.109
Severe microcephaly v2.311 GINS3 Ivone Leong gene: GINS3 was added
gene: GINS3 was added to Severe microcephaly. Sources: Literature,Expert Review Red
Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS3 were set to 35603789
Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817
Penetrance for gene: GINS3 were set to unknown
Mode of pathogenicity for gene: GINS3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v1.879 LONP1 Arina Puzriakova commented on gene: LONP1: Added 'watchlist_moi' tag to monitor recently reported association with congenital diaphragmatic hernia as highlighted in review by Zornitza Stark (Australian Genomics)
Fetal anomalies v1.879 LONP1 Arina Puzriakova Tag watchlist_moi tag was added to gene: LONP1.
Severe microcephaly v2.310 GINS2 Ivone Leong commented on gene: GINS2: This gene has been copied from the Growth failure panel (panel ID:473), as the Severe microcephaly panel appears to be a better fit for the phenotype. As there is only 1 reported case this gene has been given a Red rating.
Severe microcephaly v2.310 GINS2 Ivone Leong changed review comment from: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association and other genes associated with Meier-Gorlin syndrome has been given a Red rating in this panel due to the phenotype being not fitting the scope of this panel. Therefore, this gene has been given a Red rating.; to: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association and other genes associated with Meier-Gorlin syndrome has been given a Red rating in this panel due to the phenotype being not fitting the scope of this panel. Therefore, this gene has been given a Red rating.
Severe microcephaly v2.310 GINS2 Ivone Leong Entity copied from Growth failure in early childhood v1.107
Severe microcephaly v2.310 GINS2 Ivone Leong gene: GINS2 was added
gene: GINS2 was added to Severe microcephaly. Sources: Literature,Expert Review Red
Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS2 were set to 34353863
Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817
Penetrance for gene: GINS2 were set to unknown
Mode of pathogenicity for gene: GINS2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v1.879 LONP1 Arina Puzriakova Classified gene: LONP1 as Green List (high evidence)
Fetal anomalies v1.879 LONP1 Arina Puzriakova Gene: lonp1 has been classified as Green List (High Evidence).
Fetal anomalies v1.878 LRIT3 Arina Puzriakova Source Expert Review Red was added to LRIT3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Fetal anomalies v1.878 LONP1 Arina Puzriakova Source Expert Review Red was added to LONP1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1636 GJB2 Arina Puzriakova Source Expert Review Red was added to GJB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v2.87 CASQ1 Arina Puzriakova Source Expert Review Red was added to CASQ1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital muscular dystrophy v2.29 DPM3 Arina Puzriakova Source Expert Review Red was added to DPM3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 UQCR11 Arina Puzriakova Source Expert Review Red was added to UQCR11.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 UQCR10 Arina Puzriakova Source Expert Review Red was added to UQCR10.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 UQCC1 Arina Puzriakova Source Expert Review Red was added to UQCC1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 SDHAF4 Arina Puzriakova Source Expert Review Red was added to SDHAF4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 SDHAF3 Arina Puzriakova Source Expert Review Red was added to SDHAF3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 POLRMT Arina Puzriakova Source Expert Review Red was added to POLRMT.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 NDUFAF7 Arina Puzriakova Source Expert Review Red was added to NDUFAF7.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 GATC Arina Puzriakova Source Expert Review Red was added to GATC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 GATB Arina Puzriakova Source Expert Review Red was added to GATB.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 G6PC Arina Puzriakova Source Expert Review Red was added to G6PC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 ERAL1 Arina Puzriakova Source Expert Review Red was added to ERAL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COX6B2 Arina Puzriakova Source Expert Review Red was added to COX6B2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COX19 Arina Puzriakova Source Expert Review Red was added to COX19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COX18 Arina Puzriakova Source Expert Review Red was added to COX18.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COX17 Arina Puzriakova Source Expert Review Red was added to COX17.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COX16 Arina Puzriakova Source Expert Review Red was added to COX16.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COX11 Arina Puzriakova Source Expert Review Red was added to COX11.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COQ5 Arina Puzriakova Source Expert Review Red was added to COQ5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COA4 Arina Puzriakova Source Expert Review Red was added to COA4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 COA3 Arina Puzriakova Source Expert Review Red was added to COA3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 ATPAF1 Arina Puzriakova Source Expert Review Red was added to ATPAF1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 ATP5L2 Arina Puzriakova Source Expert Review Red was added to ATP5L2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 ATP5L Arina Puzriakova Source Expert Review Red was added to ATP5L.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 ATP5H Arina Puzriakova Source Expert Review Red was added to ATP5H.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Mitochondrial disorders v2.108 ATP5F1 Arina Puzriakova Source Expert Review Red was added to ATP5F1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Iron metabolism disorders - NOT common HFE mutations v1.34 HEPH Arina Puzriakova Source Expert Review Red was added to HEPH.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Iron metabolism disorders - NOT common HFE mutations v1.34 FTH1 Arina Puzriakova Source Expert Review Red was added to FTH1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.571 PMS2 Arina Puzriakova Source Expert Review Red was added to PMS2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.571 CFHR5 Arina Puzriakova Source Expert Review Red was added to CFHR5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.571 CFHR4 Arina Puzriakova Source Expert Review Red was added to CFHR4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.571 CFHR3 Arina Puzriakova Source Expert Review Red was added to CFHR3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.571 CFHR1 Arina Puzriakova Source Expert Review Red was added to CFHR1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Palmoplantar keratodermas v1.17 STK11 Arina Puzriakova Source Expert Review Red was added to STK11.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Epidermolysis bullosa and congenital skin fragility v1.52 EGFR Arina Puzriakova Source Expert Review Red was added to EGFR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Epidermolysis bullosa and congenital skin fragility v1.52 DSG3 Arina Puzriakova Source Expert Review Red was added to DSG3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Hypogonadotropic hypogonadism (GMS) v1.54 PLXNA3 Ivone Leong Tag Q3_22_rating tag was added to gene: PLXNA3.
Hypogonadotropic hypogonadism (GMS) v1.54 PLXNA3 Ivone Leong Classified gene: PLXNA3 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.54 PLXNA3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Based on the expert review there is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hypogonadotropic hypogonadism (GMS) v1.54 PLXNA3 Ivone Leong Gene: plxna3 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.53 SEMA3F Ivone Leong Tag Q3_22_rating tag was added to gene: SEMA3F.
Hypogonadotropic hypogonadism (GMS) v1.53 SEMA3F Ivone Leong Classified gene: SEMA3F as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.53 SEMA3F Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Based on the expert review there is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hypogonadotropic hypogonadism (GMS) v1.53 SEMA3F Ivone Leong Gene: sema3f has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.52 PLXNA3 Ivone Leong Phenotypes for gene: PLXNA3 were changed from Hypogonadotropic hypogonadism to Hypogonadotropic hypogonadism, MONDO:0018555
Hypogonadotropic hypogonadism (GMS) v1.51 SEMA3F Ivone Leong Phenotypes for gene: SEMA3F were changed from Hypogonadotropic hypogonadism to Hypogonadotropic hypogonadism, MONDO:0018555
Cerebellar hypoplasia v1.63 PRDM13 Ivone Leong Classified gene: PRDM13 as Green List (high evidence)
Cerebellar hypoplasia v1.63 PRDM13 Ivone Leong Added comment: Comment on list classification: New gene added by Julia Baptista (Faculty of Health, University of Plymouth). There is enough evidence to support a gene-disease association. Therefore this gene has been given a Green rating.
Cerebellar hypoplasia v1.63 PRDM13 Ivone Leong Gene: prdm13 has been classified as Green List (High Evidence).
Intellectual disability v3.1635 PRDM13 Ivone Leong Tag Q3_22_rating tag was added to gene: PRDM13.
Intellectual disability v3.1635 PRDM13 Ivone Leong edited their review of gene: PRDM13: Added comment: New publication. Publication reported eight individuals from four families of different origins with loss-of-function PRDM13 variants. Phenotypic findings included cerebellar hypoplasia and perinatal lethality associated with severe brainstem dysfunctions (e.g., feeding and respiratory difficulties, central apnea, bradycardia). Individuals were also reported to have severe global developmental delay. Therefore this gene should be rated Green.; Changed rating: GREEN; Changed publications to: 35390279
Differences in sex development v2.66 PRDM13 Ivone Leong Tag watchlist tag was added to gene: PRDM13.
Differences in sex development v2.66 PRDM13 Ivone Leong Added comment: Comment on publications: New publication: 35390279.
Publication reported eight individuals from four families of different origins with loss-of-function PRDM13 variants. Phenotypic findings included cerebellar hypoplasia and perinatal lethality associated with severe brainstem dysfunctions (e.g., feeding and respiratory difficulties, central apnea, bradycardia). The patients were too young to determine if disorders of sexual development was present. Therefore gene should still stay Amber.
Differences in sex development v2.66 PRDM13 Ivone Leong Publications for gene: PRDM13 were set to 34730112
Brain channelopathy v1.79 KCNMA1 Arina Puzriakova Mode of inheritance for gene: KCNMA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1635 PRDM13 Ivone Leong Entity copied from Disorders of sex development v2.65
Intellectual disability v3.1635 PRDM13 Ivone Leong gene: PRDM13 was added
gene: PRDM13 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 34730112
Phenotypes for gene: PRDM13 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Differences in sex development v2.65 PRDM13 Ivone Leong Classified gene: PRDM13 as Amber List (moderate evidence)
Differences in sex development v2.65 PRDM13 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. Based on the expert review and evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Differences in sex development v2.65 PRDM13 Ivone Leong Gene: prdm13 has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.64 PRDM13 Ivone Leong Phenotypes for gene: PRDM13 were changed from congenital hypogonadotropic hypogonadism, MONDO:0015770 to congenital hypogonadotropic hypogonadism, MONDO:0015770; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Retinal disorders v2.285 COL2A1 Ivone Leong Tag Q3_22_rating tag was added to gene: COL2A1.
Tag Q3_22_NHS_review tag was added to gene: COL2A1.
Tag Q3_22_expert_review tag was added to gene: COL2A1.
Retinal disorders v2.285 COL2A1 Ivone Leong Publications for gene: COL2A1 were set to
Retinal disorders v2.284 RGR Ivone Leong Tag Q3_22_rating tag was added to gene: RGR.
Tag Q3_22_NHS_review tag was added to gene: RGR.
Retinal disorders v2.284 RGR Ivone Leong commented on gene: RGR: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on expert review from Gavin Arno (UCL Institute of Ophthalmology/Moorfields Eye Hospital) this gene should be promoted from Amber to Green.
Retinal disorders v2.284 RGR Ivone Leong Added comment: Comment on mode of inheritance: MOI has been changed from "Both" to "Monoallelic" only based on expert review.
Retinal disorders v2.284 RGR Ivone Leong Mode of inheritance for gene: RGR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.283 RGR Ivone Leong Phenotypes for gene: RGR were changed from Eye Disorders; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa; Retinitis pigmentosa 44, 613769 to Retinitis pigmentosa 44, OMIM:613769; Retinitis pigmentosa 44, MONDO:0013414
Retinal disorders v2.282 PRPF6 Ivone Leong Phenotypes for gene: PRPF6 were changed from Retinitis pigmentosa 60; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa; Retinitis pigmentosa 60, 613983 to Retinitis pigmentosa 60, OMIM:613983; retinitis pigmentosa 60, MONDO:0013516
Retinal disorders v2.281 PRPF6 Ivone Leong Tag Q3_21_expert_review tag was added to gene: PRPF6.
Retinal disorders v2.281 PRPF6 Ivone Leong reviewed gene: PRPF6: Rating: ; Mode of pathogenicity: None; Publications: 31456290; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.281 PRPF6 Ivone Leong Publications for gene: PRPF6 were set to
Retinal disorders v2.280 POMT1 Ivone Leong Tag Q3_21_NHS_review tag was added to gene: POMT1.
Tag Q3_22_rating tag was added to gene: POMT1.
Retinal disorders v2.280 POMT1 Ivone Leong Classified gene: POMT1 as Amber List (moderate evidence)
Retinal disorders v2.280 POMT1 Ivone Leong Added comment: Comment on list classification: New gene added by Robert Henderson (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on expert review this gene should be promoted to Green.
Retinal disorders v2.280 POMT1 Ivone Leong Gene: pomt1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.279 POMT1 Ivone Leong Added comment: Comment on mode of inheritance: MOI for this gene has been changed from Monoallelic to Biallelic as this is the correct MOI.
Retinal disorders v2.279 POMT1 Ivone Leong Mode of inheritance for gene: POMT1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1634 BLOC1S1 Arina Puzriakova reviewed gene: BLOC1S1: Rating: ; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.278 POMT1 Ivone Leong Phenotypes for gene: POMT1 were changed from retinal detachment to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1, MONDO:0009364; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1, MONDO:0013159
Retinal disorders v2.277 POMT1 Ivone Leong Publications for gene: POMT1 were set to PMID:16575835; 31311558; 16887026
Corneal abnormalities v1.12 TGFBI Arina Puzriakova Tag Q1_22_MOI was removed from gene: TGFBI.
Corneal dystrophy v1.13 TGFBI Arina Puzriakova Tag Q1_22_MOI tag was added to gene: TGFBI.
Familial hypercholesterolaemia v1.30 APOE Arina Puzriakova Mode of inheritance for gene: APOE was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Familial hypercholesterolaemia v1.29 APOE Arina Puzriakova Tag Q1_22_MOI was removed from gene: APOE.
Undiagnosed metabolic disorders v1.539 DHTKD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated to biallelic to match MOI change approved on GMS Inborn errors of metabolism panel following check of MOIs on superpanel component panels.
Undiagnosed metabolic disorders v1.539 DHTKD1 Arina Puzriakova Mode of inheritance for gene: DHTKD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.538 DHTKD1 Arina Puzriakova Tag Q1_22_MOI was removed from gene: DHTKD1.
COVID-19 research v1.130 RFXANK Arina Puzriakova Phenotypes for gene: RFXANK were changed from HLA class II deficiency; Combined immunodeficiency (MHC class II deficiency, bare lymphocyte syndrome); MHC class II deficiency, complementation group B; Immunodeficiencies affecting cellular and humoral immunity; Respiratory and gastrointestinal infections, liver/biliary tract disease to MHC class II deficiency, complementation group B, OMIM:209920; HLA class II deficiency; Respiratory and gastrointestinal infections, liver/biliary tract disease; Immunodeficiencies affecting cellular and humoral immunity
Ataxia and cerebellar anomalies - childhood onset v2.299 RFXANK Arina Puzriakova Phenotypes for gene: RFXANK were changed from Progressive Ataxia and Neurologic Regression; MHC class II deficiency, complementation group B MIM#209920 to MHC class II deficiency, complementation group B, OMIM:209920; Progressive Ataxia and Neurologic Regression
Primary immunodeficiency or monogenic inflammatory bowel disease v2.570 RFXANK Arina Puzriakova Phenotypes for gene: RFXANK were changed from MHC class II deficiency, complementation group B; Combined immunodeficiency (MHC class II deficiency, bare lymphocyte syndrome); HLA class II deficiency; Respiratory and gastrointestinal infections, liver/biliary tract disease; Immunodeficiencies affecting cellular and humoral immunity to MHC class II deficiency, complementation group B, OMIM:209920; HLA class II deficiency; Respiratory and gastrointestinal infections, liver/biliary tract disease; Immunodeficiencies affecting cellular and humoral immunity
Optic neuropathy v2.70 ATG7 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.298
Optic neuropathy v2.70 ATG7 Arina Puzriakova gene: ATG7 was added
gene: ATG7 was added to Optic neuropathy. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: ATG7.
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, autosomal recessive 31, OMIM:619422
Intellectual disability v3.1634 ATG7 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.298
Intellectual disability v3.1634 ATG7 Arina Puzriakova gene: ATG7 was added
gene: ATG7 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: ATG7.
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, autosomal recessive 31, OMIM:619422
Ataxia and cerebellar anomalies - childhood onset v2.298 ATG7 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATG7.
Ataxia and cerebellar anomalies - childhood onset v2.298 ATG7 Arina Puzriakova Classified gene: ATG7 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.298 ATG7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark and based on the evidence provided this gene should be promoted to Green at the next GMS panel update. ATG7 is associated with a relevant phenotype in OMIM (MIM# 34161705) and has a 'strong' disease confidence classification for this phenotype in G2P.

Collier et al. 2021 (PMID: 34161705) identified 5 unrelated families with distinct ATG7 variants and a neurodevelopmental disorder which mainly comprised cerebellar ataxia (11/11), mild-to-severe ID (12/12), optic atrophy (7/11), among other features.
Ataxia and cerebellar anomalies - childhood onset v2.298 ATG7 Arina Puzriakova Gene: atg7 has been classified as Amber List (Moderate Evidence).
DDG2P v2.76 DMPK Eleanor Williams commented on gene: DMPK
DDG2P v2.76 CRYBB1 Eleanor Williams Tag watchlist was removed from gene: CRYBB1.
Tag Q4_21_MOI was removed from gene: CRYBB1.
DDG2P v2.76 CRYBB1 Eleanor Williams commented on gene: CRYBB1
DDG2P v2.76 ATP6V1A Eleanor Williams Tag Q3_21_rating was removed from gene: ATP6V1A.
DDG2P v2.76 ATP6V1A Eleanor Williams commented on gene: ATP6V1A
Paediatric disorders - additional genes v1.105 TMEM260 Eleanor Williams changed review comment from: Copied this gene from the Fetal anomilies/DDG2P panel on the advice on the Genomics England Clinical team as it is relevant to the Paediatric disorders super panel. If it is updated in an update of the DDG2P panel then it is not needed here, but otherwise is on this panel so that it will appear in the super panel.; to: Copied this gene from the Fetal anomilies/DDG2P panel on the advice on the Genomics England Clinical team as it is relevant to the Paediatric disorders super panel. If it is updated in an update of the DDG2P panel then it is not needed here, but otherwise is on this panel so that it will appear in the super panel.

It should be rated green following the next review.
Paediatric disorders - additional genes v1.105 TMEM260 Eleanor Williams commented on gene: TMEM260
Paediatric disorders - additional genes v1.105 TMEM260 Eleanor Williams Tag Q4_21_rating was removed from gene: TMEM260.
Tag Q3_22_rating tag was added to gene: TMEM260.
Paediatric disorders - additional genes v1.105 TMEM260 Eleanor Williams Entity copied from Fetal anomalies v1.877
Paediatric disorders - additional genes v1.105 TMEM260 Eleanor Williams gene: TMEM260 was added
gene: TMEM260 was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,PAGE DD-Gene2Phenotype
Q4_21_rating tags were added to gene: TMEM260.
Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM260 were set to 28318500; 34612517
Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, OMIM:617478; Structural heart defects and renal anomalies syndrome, MONDO:0044321
Ataxia and cerebellar anomalies - childhood onset v2.297 ATG7 Arina Puzriakova Phenotypes for gene: ATG7 were changed from Spinocerebellar ataxia, SCAR31, MIM#619422 to Spinocerebellar ataxia, autosomal recessive 31, OMIM:619422
Fetal anomalies v1.877 ZFPM2 Arina Puzriakova Classified gene: ZFPM2 as Amber List (moderate evidence)
Fetal anomalies v1.877 ZFPM2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on the evidence provided in review by Anna de Burca. Gene-disease association is classified with 'limited' confidence in G2P. Cases indicate reduced penetrance and no functional studies of variants relating to diaphragmatic hernia have been reported thus far. Gene is also associated with other phenotypes with limited support.
Fetal anomalies v1.877 ZFPM2 Arina Puzriakova Gene: zfpm2 has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.63 ZFPM2 Arina Puzriakova Phenotypes for gene: ZFPM2 were changed from 46XY sex reversal 9 616067 to 46XY sex reversal 9, OMIM:616067
Fetal anomalies v1.876 ZFPM2 Arina Puzriakova Phenotypes for gene: ZFPM2 were changed from Congenital diaphragmatic hernia to Diaphragmatic hernia 3, OMIM:610187
Familial non syndromic congenital heart disease v1.77 ZFPM2 Arina Puzriakova Mode of inheritance for gene: ZFPM2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric disorders - additional genes v1.104 ZFPM2 Arina Puzriakova Phenotypes for gene: ZFPM2 were changed from Tetralogy of Fallot to Tetralogy of Fallot, OMIM:187500
Familial non syndromic congenital heart disease v1.76 ZFPM2 Arina Puzriakova Phenotypes for gene: ZFPM2 were changed from Tetralogy of Fallot to Tetralogy of Fallot, OMIM:187500
Intellectual disability v3.1633 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 29706637; 23603762; 29671837
Early onset or syndromic epilepsy v2.548 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 23603762; 29706637
Malformations of cortical development v2.147 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 23603762; 27010057
Fetal anomalies v1.875 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 23603762; 27010057
Severe microcephaly v2.309 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 23603762; 31151415
Severe microcephaly v2.308 TUBG1 Arina Puzriakova Classified gene: TUBG1 as Amber List (moderate evidence)
Severe microcephaly v2.308 TUBG1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 11 patients with heterozygous variants in this gene have been reported in literature to date (PMIDs: 23603762; 24860126; 29706637; 31151415). Microcephaly is a predominant feature of the phenotype in majority of cases and severity is within the scope of this panel.
Severe microcephaly v2.308 TUBG1 Arina Puzriakova Gene: tubg1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.874 TUBG1 Arina Puzriakova Phenotypes for gene: TUBG1 were changed from Posteriorly predominant pachygyria and severe microcephaly to Cortical dysplasia, complex, with other brain malformations 4, OMIM:615412
Severe microcephaly v2.307 TUBG1 Arina Puzriakova Phenotypes for gene: TUBG1 were changed from to Cortical dysplasia, complex, with other brain malformations 4, OMIM:615412
Severe microcephaly v2.306 TUBG1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TUBG1.
Tag Q3_22_NHS_review tag was added to gene: TUBG1.
Intellectual disability v3.1632 TAF8 Jana Jezkova changed review comment from: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature; to: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Intellectual disability v3.1632 TAF8 Jana Jezkova gene: TAF8 was added
gene: TAF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to PMID: 35759269
Phenotypes for gene: TAF8 were set to severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy
Penetrance for gene: TAF8 were set to unknown
Review for gene: TAF8 was set to AMBER
Added comment: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Nephrocalcinosis or nephrolithiasis v2.32 SLC34A3 Detlef Bockenhauer reviewed gene: SLC34A3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16358214, 27939817, 24700880, 17968493; Phenotypes: hypercalciuria, nephrocalcinosis, nephrolithiasis, hypophosphataemia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paediatric disorders - additional genes v1.103 SIX2 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM or Gen2Phen, but it is associated with six2-related frontonasal dysplasia in MONDO / ORPHA:488437. At least 4 unrelated cases of haplosufficiency of SIX2 have been reported (three published and one in a patient reported by Julie Evans (South West Genomic Laboratory Hub)).; to: Not associated with a phenotype in OMIM or Gen2Phen, but it is associated with six2-related frontonasal dysplasia in MONDO / ORPHA:488437. At least 4 unrelated cases of haplosufficiency of SIX2 have been reported (three published and one in a patient reported by Julie Evans (South West Genomic Laboratory Hub)). So far the variants associated with SIX2 are deletions of varying sizes, with the common feature that they all encompass the SIX2 locus.
Paediatric disorders - additional genes v1.103 SIX2 Sarah Leigh Tag structural-variant tag was added to gene: SIX2.
Paediatric disorders - additional genes v1.103 SIX2 Sarah Leigh Phenotypes for gene: SIX2 were changed from Frontonasal dysplasia; ptosis; hearing loss to six2-related frontonasal dysplasia, MONDO:0044628
Paediatric disorders - additional genes v1.102 SIX2 Sarah Leigh edited their review of gene: SIX2: Added comment: Not associated with a phenotype in OMIM or Gen2Phen, but it is associated with six2-related frontonasal dysplasia in MONDO / ORPHA:488437. At least 4 unrelated cases of haplosufficiency of SIX2 have been reported (three published and one in a patient reported by Julie Evans (South West Genomic Laboratory Hub)).; Changed rating: GREEN; Changed phenotypes to: six2-related frontonasal dysplasia, MONDO:0044628
Paediatric disorders - additional genes v1.102 SIX2 Sarah Leigh Classified gene: SIX2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.102 SIX2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Paediatric disorders - additional genes v1.102 SIX2 Sarah Leigh Gene: six2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.101 SIX2 Sarah Leigh Tag Q3_22_rating tag was added to gene: SIX2.
Tag Q3_22_NHS_review tag was added to gene: SIX2.
Paediatric disorders - additional genes v1.101 SIX2 Sarah Leigh Publications for gene: SIX2 were set to PMID: 27383657; 29315086; 26581443
Paediatric disorders - additional genes v1.100 SIX2 Sarah Leigh Classified gene: SIX2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.100 SIX2 Sarah Leigh Gene: six2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.86 HACD1 Sarah Leigh reviewed gene: HACD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1632 STT3A Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic'. Congenital disorder of glycosylation due to monoallelic variants in STT3A has been identified in at least 16 patients from 9 families (PMID: 34653363). Phenotypes included mild-moderate ID/DD in 10/16 subjects.
Intellectual disability v3.1632 STT3A Arina Puzriakova Mode of inheritance for gene: STT3A was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1631 STT3A Arina Puzriakova Tag Q3_22_MOI tag was added to gene: STT3A.
Likely inborn error of metabolism v2.262 STT3A Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic' - congenital disorder of glycosylation due to STT3A has been identified in at least 3 families with biallelic variants (PMIDs: 23842455; 30701557; 28424003) and 9 families with monoallelic variants (PMID: 34653363)
Likely inborn error of metabolism v2.262 STT3A Arina Puzriakova Mode of inheritance for gene: STT3A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.261 STT3A Arina Puzriakova Tag Q3_22_rating tag was added to gene: STT3A.
Likely inborn error of metabolism v2.261 STT3A Arina Puzriakova Publications for gene: STT3A were set to 23842455
Intellectual disability v3.1631 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from Congenital disorder of glycosylation, type Iw, 615596 to Congenital disorder of glycosylation, type Iw, autosomal dominant, OMIM:619714; Congenital disorder of glycosylation, type Iw, autosomal recessive, OMIM:615596
Likely inborn error of metabolism v2.260 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from ?Congenital disorder of glycosylation, type Iw 615596 to Congenital disorder of glycosylation, type Iw, autosomal dominant, OMIM:619714; Congenital disorder of glycosylation, type Iw, autosomal recessive, OMIM:615596
Intellectual disability v3.1630 STT3A Arina Puzriakova Publications for gene: STT3A were set to 23842455; 28424003; 30701557
DDG2P v2.76 CLTC Anna de Burca reviewed gene: CLTC: Rating: ; Mode of pathogenicity: None; Publications: PubMed: 29100083; Phenotypes: Developmental & epileptic encephalopathies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital disorders of glycosylation v2.91 STT3A Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from biallelic to both mono- and biallelic at the next GMS panel update as per review by Zornitza Stark. Both MOIs are also now recognised in OMIM.
Congenital disorders of glycosylation v2.91 STT3A Arina Puzriakova Mode of inheritance for gene: STT3A was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v2.90 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from Congenital disorder of glycosylation, type Iw, 615596 to Congenital disorder of glycosylation, type Iw, autosomal dominant, OMIM:619714; Congenital disorder of glycosylation, type Iw, autosomal recessive, OMIM:615596
Congenital disorders of glycosylation v2.89 STT3A Arina Puzriakova Publications for gene: STT3A were set to 23842455; 28424003; 30701557
Congenital disorders of glycosylation v2.88 STT3A Arina Puzriakova Tag Q3_22_MOI tag was added to gene: STT3A.
Congenital disorders of glycosylation v2.88 OSTC Arina Puzriakova Classified gene: OSTC as Red List (low evidence)
Congenital disorders of glycosylation v2.88 OSTC Arina Puzriakova Added comment: Comment on list classification: Single case reported to date, as per review by Zornitza Stark. Rating Red until further cases emerge.
Congenital disorders of glycosylation v2.88 OSTC Arina Puzriakova Gene: ostc has been classified as Red List (Low Evidence).
Intellectual disability v3.1629 EDEM3 Arina Puzriakova Entity copied from Congenital disorders of glycosylation v2.87
Intellectual disability v3.1629 EDEM3 Arina Puzriakova gene: EDEM3 was added
gene: EDEM3 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: EDEM3.
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to Congenital disorder of glycosylation, type 2V, OMIM:619493
Congenital disorders of glycosylation v2.87 EDEM3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: EDEM3.
Congenital disorders of glycosylation v2.87 EDEM3 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

EDEM3 is associated with a relevant phenotype in OMIM (MIM# 619493) and G2P with a 'strong' confidence level assertion.

12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms.
Congenital disorders of glycosylation v2.87 EDEM3 Arina Puzriakova Classified gene: EDEM3 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.87 EDEM3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms.
Congenital disorders of glycosylation v2.87 EDEM3 Arina Puzriakova Gene: edem3 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v2.86 EDEM3 Arina Puzriakova Phenotypes for gene: EDEM3 were changed from Congenital disorder of glycosylation to Congenital disorder of glycosylation, type 2V, OMIM:619493
Primary immunodeficiency or monogenic inflammatory bowel disease v2.569 STAT6 Arina Puzriakova Classified gene: STAT6 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.569 STAT6 Arina Puzriakova Added comment: Comment on list classification: Two unrelated patients with early-life onset of allergic immune dysregulation described in preprint by Sharma et al. as per review by Boaz Palterer. Red rating may be reconsidered following peer review of paper but additional cases would be required to reach a diagnostic level of evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.569 STAT6 Arina Puzriakova Gene: stat6 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.568 STAT6 Arina Puzriakova Tag watchlist tag was added to gene: STAT6.
Pulmonary Fibrosis, Familial v0.10 HCK Arina Puzriakova Entity copied from Primary immunodeficiency v2.568
Pulmonary Fibrosis, Familial v0.10 HCK Arina Puzriakova gene: HCK was added
gene: HCK was added to Pulmonary fibrosis familial. Sources: Literature,Expert Review Red
Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HCK were set to 34536415
Phenotypes for gene: HCK were set to Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease
Penetrance for gene: HCK were set to unknown
Mode of pathogenicity for gene: HCK was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v2.568 HCK Arina Puzriakova Mode of inheritance for gene: HCK was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.567 HCK Arina Puzriakova Classified gene: HCK as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.567 HCK Arina Puzriakova Added comment: Comment on list classification: Single case reported to date as per review by Boaz Palterer. Rating Red until further cases emerge.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.567 HCK Arina Puzriakova Gene: hck has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.566 TLR8 Arina Puzriakova Publications for gene: TLR8 were set to 33512449; 34981838
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Classified gene: TLR8 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Added comment: Comment on list classification: Overall at least 7 unrelated families have been reported which support an association of TLR8 with immune dysfunction and autoinflammation, of which two families harboured germline variants. Functional data, including in vitro and animal model studies, corroborate pathogenicity of TLR8 variants. Therefore this gene can now be promoted to Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Gene: tlr8 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.564 TLR8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TLR8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.564 TLR8 Arina Puzriakova Publications for gene: TLR8 were set to https://doi.org/10.1182/blood.2020009620
Primary immunodeficiency or monogenic inflammatory bowel disease v2.563 TLR8 Arina Puzriakova Mode of inheritance for gene: TLR8 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.562 TLR8 Arina Puzriakova Phenotypes for gene: TLR8 were changed from neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure to Immunodeficiency 98 with autoinflammation, X-linked, OMIM:301078
Primary immunodeficiency or monogenic inflammatory bowel disease v2.561 CRACR2A Arina Puzriakova Classified gene: CRACR2A as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.561 CRACR2A Arina Puzriakova Added comment: Comment on list classification: Single case reported to date, as per review by Zornitza Stark. Rating Red until further cases emerge.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.561 CRACR2A Arina Puzriakova Gene: cracr2a has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.560 ANGPT1 Arina Puzriakova Classified gene: ANGPT1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.560 ANGPT1 Arina Puzriakova Added comment: Comment on list classification: To date only a single family has been reported but with several lines of evidence such as multigenerational segregation and functional data that provides a plausible mechanism of disease. At least one more case is needed to corroborate this gene-disease association, and therefore Rating Amber with a watchlist tag in anticipation of further cases emerging.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.560 ANGPT1 Arina Puzriakova Gene: angpt1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.559 ANGPT1 Arina Puzriakova reviewed gene: ANGPT1: Rating: ; Mode of pathogenicity: None; Publications: 28601681, 30689269; Phenotypes: Angioedema, hereditary, 5, OMIM:61936; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.559 ANGPT1 Arina Puzriakova Publications for gene: ANGPT1 were set to 28601681
Primary immunodeficiency or monogenic inflammatory bowel disease v2.558 ANGPT1 Arina Puzriakova Tag watchlist tag was added to gene: ANGPT1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.558 ANGPT1 Arina Puzriakova Phenotypes for gene: ANGPT1 were changed from Hereditary Angioedema to Angioedema, hereditary, 5, OMIM:619361
Early onset or syndromic epilepsy v2.547 PPFIBP1 Konstantinos Varvagiannis gene: PPFIBP1 was added
gene: PPFIBP1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision
Penetrance for gene: PPFIBP1 were set to Complete
Review for gene: PPFIBP1 was set to GREEN
Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below.

----

Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features.

All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features.

The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications.

Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description.

9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed.
The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling.

PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport.

A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article).

Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect.

----

There is currently no PPFIBP1 - associated phenotype in OMIM / G2P.
SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071).
In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print.
Sources: Literature
Intellectual disability v3.1628 PPFIBP1 Konstantinos Varvagiannis gene: PPFIBP1 was added
gene: PPFIBP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision
Penetrance for gene: PPFIBP1 were set to Complete
Review for gene: PPFIBP1 was set to GREEN
Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below.

----

Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features.

All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features.

The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications.

Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description.

9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed.
The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling.

PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport.

A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article).

Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect.

----

There is currently no PPFIBP1 - associated phenotype in OMIM / G2P.
SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071).
In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print.
Sources: Literature
Intellectual disability v3.1628 SEMA3E Sarah Leigh gene: SEMA3E was added
gene: SEMA3E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SEMA3E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEMA3E were set to 35628442
Phenotypes for gene: SEMA3E were set to Severe Intellectual Disability with Cognitive Regression
Review for gene: SEMA3E was set to AMBER
Added comment: Not associated with a phenotype in OMIM or Gen2Phen. One variant has been reported in a case of Severe Intellectual Disability with Cognitive Regression (PMID: 35628442). PMID: 35628442 also describes functional studies which show that this variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues, furthermore, SEMA3E was revealed to be expressed during human brain development.
Sources: Literature
Bleeding and platelet disorders v1.43 APOLD1 Sarah Leigh gene: APOLD1 was added
gene: APOLD1 was added to Bleeding and platelet disorders. Sources: Literature
Mode of inheritance for gene: APOLD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: APOLD1 were set to 35638551
Phenotypes for gene: APOLD1 were set to inherited bleeding disorder
Review for gene: APOLD1 was set to RED
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. One heterozygous variant (NM_001130415; c.145_146delinsTA; p.R49*) has been reported to segregate with inherited bleeding in three sisters.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 EP300 Boaz Palterer gene: EP300 was added
gene: EP300 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: EP300 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EP300 were set to 32594341
Phenotypes for gene: EP300 were set to Rubinstein-Taybi Syndrome; Hypogammaglobulinemia; short stature; Intellectual disability; broad thumbs and first toes; highly arched eyebrows; long eyelashes; downslanting palpebral fissures; convex nasal ridge; low hanging columella; highly arched palate; micrognathia
Penetrance for gene: EP300 were set to unknown
Review for gene: EP300 was set to GREEN
Added comment: Saettini et al. reviewed immunological features of Rubinstein-Taybi Syndrome and found: "Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. ", making it a relevant phenotype for this panel.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 CREBBP Boaz Palterer gene: CREBBP was added
gene: CREBBP was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CREBBP were set to 32594341
Phenotypes for gene: CREBBP were set to Rubinstein-Taybi Syndrome; Hypogammaglobulinemia; short stature; Intellectual disability; broad thumbs and first toes; highly arched eyebrows; long eyelashes; downslanting palpebral fissures; convex nasal ridge; low hanging columella; highly arched palate; micrognathia
Penetrance for gene: CREBBP were set to unknown
Review for gene: CREBBP was set to GREEN
Added comment: Saettini et al. reviewed immunological features of Rubinstein-Taybi Syndrome and found: "Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. ", making it a relevant phenotype for this panel.
Sources: Literature
DDG2P v2.76 EMC1 Dmitrijs Rots reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35234901; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1627 EMC1 Dmitrijs Rots reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35234901; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1627 SLC1A2 Sarah Leigh Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41, 617105; Intellectual disability to Epileptic encephalopathy, early infantile, 41, OMIM:617105; developmental and epileptic encephalopathy, 41, MONDO:0014916
Early onset or syndromic epilepsy v2.547 SLC1A2 Sarah Leigh Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41, 617105 to Epileptic encephalopathy, early infantile, 41, OMIM:617105; developmental and epileptic encephalopathy, 41, MONDO:0014916
Early onset or syndromic epilepsy v2.546 SLC1A2 Sarah Leigh Publications for gene: SLC1A2 were set to 27476654; 28777935; 23934111; 9180080; 28915517
Early onset or syndromic epilepsy v2.545 SLC1A2 Sarah Leigh changed review comment from: PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function. In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other.; to: PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function, possibly by abnormal channel conductance (PMID: 27445142). In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other. Clearly further functional studies will be required to clafiry the mechanisms by which SLC1A2 variants result in epilepsy and other phenotypic features.
Retinal disorders v2.276 RGR Gavin Arno edited their review of gene: RGR: Added comment: The evidence for dominant disease is sufficient I think, the late frameshift is seen in several families now. There is no current data to support recessive disease; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric motor neuronopathies v1.79 SNRPN Arina Puzriakova Publications for gene: SNRPN were set to 10802660; 8723064
Laterality disorders and isomerism v1.51 DAND5 Arina Puzriakova gene: DAND5 was added
gene: DAND5 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: DAND5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAND5 were set to 34215651
Phenotypes for gene: DAND5 were set to Heterotaxy syndrome
Added comment: In a single individual with heterotaxy and congenital heart defects of L-R patterning, Bolkier et al., 2022 (PMID:34215651) identified a homozygous truncating (c.396_397dupCT) variant in the DAND5 gene.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.58 TTC25 Arina Puzriakova Phenotypes for gene: TTC25 were changed from Ciliary dyskinesia, primary 35, 617092 to Ciliary dyskinesia, primary, 35, OMIM:617092
Respiratory ciliopathies including non-CF bronchiectasis v1.57 TTC25 Arina Puzriakova Publications for gene: TTC25 were set to 27486780
Laterality disorders and isomerism v1.50 TTC25 Arina Puzriakova Phenotypes for gene: TTC25 were changed from Ciliary dyskinesia, primary, 35, 617092 to Ciliary dyskinesia, primary, 35, OMIM:617092
Laterality disorders and isomerism v1.49 TTC25 Arina Puzriakova Publications for gene: TTC25 were set to 27486780
Laterality disorders and isomerism v1.48 TTC25 Arina Puzriakova Classified gene: TTC25 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.48 TTC25 Arina Puzriakova Added comment: Comment on list classification: Biallelic variants cause a primary ciliary dyskinesia which is associated with laterality defects - at least 6 unrelated families reported in literature (PMID: 27486780; 33715250; 33746037; 34215651)
This evidence now supports a Green rating on this panel and so this gene should be updated accordingly at the next GMS panel update.
Laterality disorders and isomerism v1.48 TTC25 Arina Puzriakova Gene: ttc25 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.47 TTC25 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TTC25.
Dystonia, chorea or related movement disorder, childhood onset v1.240 HECW2 Arina Puzriakova Classified gene: HECW2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.240 HECW2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update. Motor dysfunction is a key feature in majority of cases and of all individuals aged 5 years or older, only 7/12 could walk, although often with limited capacity. Therefore, inclusion of HECW2 on this panel could present potential diagnostic benefit.
Dystonia, chorea or related movement disorder, childhood onset v1.240 HECW2 Arina Puzriakova Gene: hecw2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.276 COL2A1 Robert Henderson reviewed gene: COL2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32867104, 9091360, 30130436; Phenotypes: Stickler syndrome, retinal detachment, cortical cataract, congenital myopia, vitreous abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.239 HECW2 Arina Puzriakova gene: HECW2 was added
gene: HECW2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Q3_22_rating tags were added to gene: HECW2.
Mode of inheritance for gene: HECW2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HECW2 were set to 27389779; 27334371; 34321324
Phenotypes for gene: HECW2 were set to Neurodevelopmental disorder with hypotonia, seizures, and absent language, OMIM:617268
Review for gene: HECW2 was set to GREEN
Added comment: Acharya et al., 2022 (PMID: 34321324) released a review of 35 previously published and new unpublished cases harbouring HECW2 variants. Clinical characteristics in all individuals included ID/DD and hypotonia with or without spasticity. The review also highlighted motor coordination/movement deficits in 21/28 subjects (75%). Stereotypic movements were the most common (15) but dystonia (4) and chorea (3) are also reported.
Sources: Literature
Early onset or syndromic epilepsy v2.545 HECW2 Arina Puzriakova Publications for gene: HECW2 were set to 27389779; 27334371; 34321324
Intellectual disability v3.1626 HECW2 Arina Puzriakova Publications for gene: HECW2 were set to 25529582
Early onset or syndromic epilepsy v2.544 HECW2 Arina Puzriakova Publications for gene: HECW2 were set to 27389779; 27334371
Epidermolysis bullosa and congenital skin fragility v1.51 SPINK5 Arina Puzriakova commented on gene: SPINK5
Epidermolysis bullosa and congenital skin fragility v1.51 SPINK5 Arina Puzriakova Tag Q3_22_expert_review tag was added to gene: SPINK5.
White matter disorders and cerebral calcification - childhood onset v1.239 MAL Sarah Leigh Entity copied from Inherited white matter disorders v1.159
White matter disorders and cerebral calcification - childhood onset v1.239 MAL Sarah Leigh gene: MAL was added
gene: MAL was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Leukodystrophy, adult onset v1.42 MAL Sarah Leigh Entity copied from Inherited white matter disorders v1.159
Leukodystrophy, adult onset v1.42 MAL Sarah Leigh gene: MAL was added
gene: MAL was added to White matter disorders - adult onset. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Dystonia, chorea or related movement disorder, childhood onset v1.238 MAL Sarah Leigh reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1625 MAL Sarah Leigh reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inherited white matter disorders v1.159 MAL Sarah Leigh reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1625 MAL Sarah Leigh Classified gene: MAL as Amber List (moderate evidence)
Intellectual disability v3.1625 MAL Sarah Leigh Gene: mal has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.238 MAL Sarah Leigh Classified gene: MAL as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.238 MAL Sarah Leigh Gene: mal has been classified as Amber List (Moderate Evidence).
Inherited white matter disorders v1.159 MAL Sarah Leigh Classified gene: MAL as Amber List (moderate evidence)
Inherited white matter disorders v1.159 MAL Sarah Leigh Gene: mal has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.543 DNM1 Arina Puzriakova Tag watchlist was removed from gene: DNM1.
Tag watchlist_moi tag was added to gene: DNM1.
Early onset or syndromic epilepsy v2.543 DNM1 Arina Puzriakova changed review comment from: Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. If this is a genuine association, biallelic cases would still be picked by the Genomics England pipeline under this MOI. Added watchlist tag in anticipation of further biallelic cases emerging.; to: Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. Added watchlist tag in anticipation of further biallelic cases emerging.
Dystonia, chorea or related movement disorder, childhood onset v1.237 MAL Julia Baptista gene: MAL was added
gene: MAL was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Review for gene: MAL was set to AMBER
Added comment: Single consanguineous family reported with two affected children (DD and nystagmus). New onset ataxia and cerebellar volume loss with patchy dysmyelination. Homozygous missense variant identified by exome analysis segregated with the condition. Functional data suggested that p.(Ala109Asp) severely affects protein folding of MAL, leading to mislocalization in the ER.
Sources: Literature
Intellectual disability v3.1624 MAL Julia Baptista gene: MAL was added
gene: MAL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Review for gene: MAL was set to AMBER
Added comment: Single consanguineous family reported with two affected children (DD and nystagmus). New onset ataxia and cerebellar volume loss with patchy dysmyelination. Homozygous missense variant identified by exome analysis segregated with the condition. Functional data suggested that p.(Ala109Asp) severely affects protein folding of MAL, leading to mislocalization in the ER.
Sources: Literature
Inherited white matter disorders v1.158 MAL Julia Baptista gene: MAL was added
gene: MAL was added to Inherited white matter disorders. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Review for gene: MAL was set to AMBER
Added comment: Single consanguineous family reported with two affected children (DD and nystagmus). New onset ataxia and cerebellar volume loss with patchy dysmyelination. Homozygous missense variant identified by exome analysis segregated with the condition. Functional data suggested that p.(Ala109Asp) severely affects protein folding of MAL, leading to mislocalization in the ER.
Sources: Literature
Intellectual disability v3.1624 GNB2 Arina Puzriakova Phenotypes for gene: GNB2 were changed from Intellectual disability to Neurodevelopmental disorder with hypotonia and dysmorphic facies, OMIM:619503
Cystic kidney disease v2.45 PAX2 Natalie Forrester gene: PAX2 was added
gene: PAX2 was added to Cystic kidney disease. Sources: NHS GMS
Mode of inheritance for gene: PAX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAX2 were set to PMID: 33746522; 16049068; 22213154
Phenotypes for gene: PAX2 were set to cystic renal disease
Penetrance for gene: PAX2 were set to unknown
Review for gene: PAX2 was set to GREEN
gene: PAX2 was marked as current diagnostic
Added comment: PAX2 (OMIM 167409) is associated with Papillorenal syndrome, one feature of which can be renal cysts. Ocular involvement is common, but it is also noted that it can be mild/undetectable. In our NHSE lab we have identified a novel missense variant in a patient with cystic dysplastic kidneys. This was detected by Exomiser tiering by WGS and was reported as likely pathogenic. There are many reports in the literature of its association with renal disease, including cysts, and I expect that is the reason it is included on the R195 and R257 panels, but it also seems appropriate to be included on R193 where currently it is not even amber or red.
Sources: NHS GMS
Renal tubulopathies v2.54 RRAGD Detlef Bockenhauer gene: RRAGD was added
gene: RRAGD was added to Renal tubulopathies. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to PMID: 34607910
Phenotypes for gene: RRAGD were set to hypomagnesaemia; cardiomyopathy
Penetrance for gene: RRAGD were set to Complete
Mode of pathogenicity for gene: RRAGD was set to Other
Review for gene: RRAGD was set to GREEN
Added comment: publication from Nov 2021, reporting on 8 unrelated children with a phenotype of hypokalaemia, hypomagnesaemia and dilative cardiomyopathy who had mostly de novo heterozygous variants in RRAGD. Also identified a family where hypomagnesaemia segregated with a heterozygous variant in RRAGD in 8 members.
In vitro studies of variants are consistent with a gain-of-function, i.e. mTOR activation
Sources: Literature
Fetal anomalies v1.873 WNT7B Julia Baptista gene: WNT7B was added
gene: WNT7B was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: WNT7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT7B were set to 35790350
Phenotypes for gene: WNT7B were set to Pulmonary hypoplasia; Diaphragmatic anomalies; Anophthalmia/Microphthalmia; Cardiac defects
Review for gene: WNT7B was set to GREEN
Added comment: One homozygous nonsense variant identified in family 1. Compound heterozygous missense and nonsense variants identified in two affected fetuses in family 2. A third family with limited phenotypic information available, with parents heterozygous for the same nonsense variant, p. (Arg98Ter), identified in family 1, but no segregation studies in the affected.
Animal studies in Danio rerio were supportive.
Lung hypoplasia with tracheal, ocular, cardiac, and renal defects.
Sources: Expert Review
Differences in sex development v2.62 SRY Eleanor Williams commented on gene: SRY
Early onset or syndromic epilepsy v2.543 CERS1 Helen Lord reviewed gene: CERS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33798445, 30800706, 27618929, 24782409; Phenotypes: progressive myoclonic epilepy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.543 FAR1 Helen Lord reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33239752, 25439727, 33586168, 28454995; Phenotypes: cataracts, spastic paraparesis and speech delay & peroxisomal fatty Acyl-CoA reductase I disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 C2orf69 Boaz Palterer gene: C2orf69 was added
gene: C2orf69 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 33945503; 34038740
Phenotypes for gene: C2orf69 were set to hypomyelination; microcephaly; liver dysfunction; autoinflammation; leukoencephalopathy
Penetrance for gene: C2orf69 were set to unknown
Review for gene: C2orf69 was set to GREEN
Added comment: Lausberg et al. dentified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals from 5 kindreds with biallelic C2orf69 variants, presenting with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation.
Wong et al. described 20 subjects from 5 kindreds with biallelic variants and a similar phenotype.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 ATAD3A Boaz Palterer gene: ATAD3A was added
gene: ATAD3A was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 34387651
Phenotypes for gene: ATAD3A were set to Developmental delay; Hypotonia; Dystonia; Systemic sclerosis; Autoimmunity; Contractures; Basal ganglia calcifications; Interferonopathy
Penetrance for gene: ATAD3A were set to unknown
Review for gene: ATAD3A was set to GREEN
Added comment: Leppeley et al. described 8 patients across 7 kindreds (one inherited and 7 de novo), with mono or biallelic variants in ATAD3A. Patients presented with a wide clinical spectrum and all presented elevated IFN signature.
Functional data provided: "Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA."
Sources: Literature
Malformations of cortical development v2.146 WNK3 Arina Puzriakova Classified gene: WNK3 as Amber List (moderate evidence)
Malformations of cortical development v2.146 WNK3 Arina Puzriakova Added comment: Comment on list classification: Brain phenotypes in cases reported to date are varied and non-specific. Therefore, rating Amber with a watchlist tag to allow monitoring for future cases which may indicate whether brain malformations are a prominent features of this disorder.
Malformations of cortical development v2.146 WNK3 Arina Puzriakova Gene: wnk3 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.145 WNK3 Arina Puzriakova gene: WNK3 was added
gene: WNK3 was added to Malformations of cortical development. Sources: Literature
watchlist tags were added to gene: WNK3.
Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WNK3 were set to 35678782
Phenotypes for gene: WNK3 were set to Intellectual disability, MONDO:0001071
Added comment: Kury et al. 2022 (PMID: 35678782) reported 14 males from 6 unrelated families with hemizygous variants (3 LOF and 3 missense, predicted pathogenic) in the WNK3 gene. All (14/14) had DD/ID and variable other associations including seizures (5/13), mild microcephaly (6/13, ranging -2 to -2.4 SD) and structural brain malformations (7/10). Heterozygous mothers were all asymptomatic.

Brain imaging in 4 families that had anomalies showed F1) polymicrogyria in two sibs, F2) mild cerebral atrophy and bilateral periventricular white matter hypersignal, F3) three patients with subcortical cerebral atrophy, dilation of lateral ventricles, and F4) symmetric T2 prolongation involving the deep gray structures, central tegmental tracts and dentate nuclei.
Sources: Literature
Inherited polyposis and early onset colorectal cancer - germline testing v1.32 MBD4 Arina Puzriakova changed review comment from: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-down cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.; to: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.
Inherited predisposition to acute myeloid leukaemia (AML) v1.24 MBD4 Arina Puzriakova changed review comment from: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-down cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.; to: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.
Haematological malignancies cancer susceptibility v2.34 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from AML, colonic polyps, uveal melanoma, glioblastoma to Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Haematological malignancies cancer susceptibility v2.33 MBD4 Arina Puzriakova Tag Q3_22_expert_review tag was added to gene: MBD4.
Haematological malignancies cancer susceptibility v2.33 MBD4 Arina Puzriakova commented on gene: MBD4: Re-tagging on this panel following a separate Green expert review on a different GMS panel (R347, R211) to ensure that if the decision is made to include the gene, all panels are appropriately updated.
Haematological malignancies cancer susceptibility v2.33 MBD4 Arina Puzriakova changed review comment from: Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal, 2/5 family), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.; to: Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal, 2 family), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.
Haematological malignancies cancer susceptibility v2.33 MBD4 Arina Puzriakova changed review comment from: Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.; to: Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal, 2/5 family), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.
Haematological malignancies cancer susceptibility v2.33 MBD4 Arina Puzriakova edited their review of gene: MBD4: Added comment: Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.; Changed publications to: 12417741, 30049810, 32239153, 35460607; Changed phenotypes to: Multi-organ tumour predisposition syndrome, Adenomatous colorectal polyposis, Colorectal cancer, Acute myeloid leukemia, Uveal melanoma
Inherited polyposis and early onset colorectal cancer - germline testing v1.32 MBD4 Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v1.32 MBD4 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-down cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.
Inherited polyposis and early onset colorectal cancer - germline testing v1.32 MBD4 Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
Inherited polyposis and early onset colorectal cancer - germline testing v1.31 MBD4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: MBD4.
Tag Q3_22_NHS_review tag was added to gene: MBD4.
Tag Q3_22_expert_review tag was added to gene: MBD4.
Inherited polyposis and early onset colorectal cancer - germline testing v1.31 MBD4 Arina Puzriakova Entity copied from GI tract tumours v1.22
Inherited polyposis and early onset colorectal cancer - germline testing v1.31 MBD4 Arina Puzriakova gene: MBD4 was added
gene: MBD4 was added to Inherited polyposis. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: MBD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBD4 were set to 12417741; 30049810; 32239153; 35460607
Phenotypes for gene: MBD4 were set to Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Penetrance for gene: MBD4 were set to Complete
GI tract tumours v1.22 MBD4 Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
GI tract tumours v1.22 MBD4 Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
GI tract tumours v1.21 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from polyposis; CRC; AML; MDS; UVM to Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
GI tract tumours v1.20 MBD4 Arina Puzriakova Publications for gene: MBD4 were set to 35460607
GI tract tumours v1.19 MBD4 Arina Puzriakova reviewed gene: MBD4: Rating: ; Mode of pathogenicity: None; Publications: 12417741, 30049810, 32239153, 35460607; Phenotypes: Multi-organ tumour predisposition syndrome, Adenomatous colorectal polyposis, Colorectal cancer, Acute myeloid leukemia, Uveal melanoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited predisposition to acute myeloid leukaemia (AML) v1.24 MBD4 Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
Inherited predisposition to acute myeloid leukaemia (AML) v1.24 MBD4 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for GMS expert review to determine the suitability of MBD4 for malignancy predisposition testing.

MBD4 was first added by an external reviewer to the 'Haematological malignancies cancer susceptibility' panel (https://panelapp.genomicsengland.co.uk/panels/59/gene/MBD4/), however after GMS consideration it was decided that it should remain amber (v2.23).

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-down cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Given that there are now two separate Green clinical reviews suggesting this gene, it will again be flagged for further GMS review.
Inherited predisposition to acute myeloid leukaemia (AML) v1.24 MBD4 Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
Inherited predisposition to acute myeloid leukaemia (AML) v1.23 MBD4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: MBD4.
Tag Q3_22_NHS_review tag was added to gene: MBD4.
Tag Q3_22_expert_review tag was added to gene: MBD4.
Inherited predisposition to acute myeloid leukaemia (AML) v1.23 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from polyposis; CRC; AML; MDS; UVM to Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Inherited predisposition to acute myeloid leukaemia (AML) v1.22 MBD4 Arina Puzriakova Publications for gene: MBD4 were set to 35460607
Inherited predisposition to acute myeloid leukaemia (AML) v1.21 MBD4 Arina Puzriakova reviewed gene: MBD4: Rating: ; Mode of pathogenicity: None; Publications: 12417741, 30049810, 32239153, 35460607; Phenotypes: Multi-organ tumour predisposition syndrome, Adenomatous colorectal polyposis, Colorectal cancer, Acute myeloid leukemia, Uveal melanoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.43 MTM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Rare manifesting females have been reported in literature (PMID: 10323249; 11552027; 12707446; 15883335) as well as by review of Helen Brittain (Genomics England Clinical Team) providing details of a case identified in clinic - “Participant (female singleton) has a phenotype of distal myopathies with facial hypotonia, limb weakness, progressive weakness and abnormality of muscle morphology among the HPO terms".

MOI should therefore be updated form XLR to XLD at the next GMS review.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.43 MTM1 Arina Puzriakova Mode of inheritance for gene: MTM1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital myopathy v2.86 MTM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Rare manifesting females have been reported in literature (PMID: 10323249; 11552027; 12707446; 15883335) as well as by review of Helen Brittain (Genomics England Clinical Team) providing details of a case identified in clinic - “Participant (female singleton) has a phenotype of distal myopathies with facial hypotonia, limb weakness, progressive weakness and abnormality of muscle morphology among the HPO terms".

MOI should therefore be updated form XLR to XLD at the next GMS review.
Congenital myopathy v2.86 MTM1 Arina Puzriakova Mode of inheritance for gene: MTM1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.873 MTM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Rare manifesting females have been reported, including a heterozygous female with prenatal/neonatal onset (PMID: 12707446). MOI should therefore be updated form XLR to XLD at the next GMS review.
Fetal anomalies v1.873 MTM1 Arina Puzriakova Mode of inheritance for gene: MTM1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.42 MTM1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: MTM1.
Congenital myopathy v2.85 MTM1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: MTM1.
Fetal anomalies v1.872 MTM1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: MTM1.
Hydrocephalus v2.131 MTM1 Arina Puzriakova Mode of inheritance for gene: MTM1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v1.872 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from MYOTUBULAR MYOPATHY, X-LINKED to Myopathy, centronuclear, X-linked, OMIM:310400
Arthrogryposis v3.160 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from X-linked myotubular myopathy; Myotubular myopathy, X-linked, 310400 to Myopathy, centronuclear, X-linked, OMIM:310400
Intellectual disability v3.1623 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from X-linked Myotubular Myopathy; MYOTUBULAR MYOPATHY, X-LINKED to Myopathy, centronuclear, X-linked, OMIM:310400
Hydrocephalus v2.130 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from Myotubular myopathy, X-linked, OMIM:310400 to Myopathy, centronuclear, X-linked, OMIM:310400
Congenital myopathy v2.85 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from Myopathy, centronuclear, X-linked 310400 to Myopathy, centronuclear, X-linked, OMIM:310400
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.42 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from Myotubular myopathy, X-linked, 310400 to Myopathy, centronuclear, X-linked, OMIM:310400
Congenital myopathy v2.84 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from X-linked myotubular myopathy; Myotubular myopathy, X-linked, 310400 to Myopathy, centronuclear, X-linked 310400
Early onset or syndromic epilepsy v2.543 WNK3 Arina Puzriakova changed review comment from: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families, all presenting with ID in association with variants in the WNK3 gene.; to: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families with variants in the WNK3 gene, of which at least 5 subjects (3 families) displayed seizures.
Early onset or syndromic epilepsy v2.543 WNK3 Arina Puzriakova Entity copied from Intellectual disability v3.1622
Early onset or syndromic epilepsy v2.543 WNK3 Arina Puzriakova gene: WNK3 was added
gene: WNK3 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber
Q3_22_rating tags were added to gene: WNK3.
Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WNK3 were set to 26350204; 35678782
Phenotypes for gene: WNK3 were set to X-linked intellectual disability, MONDO:0100284
Penetrance for gene: WNK3 were set to Complete
Intellectual disability v3.1622 WNK3 Arina Puzriakova Mode of inheritance for gene: WNK3 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 v3.1621 WNK3 Arina Puzriakova Publications for gene: WNK3 were set to 26350204
Intellectual disability v3.1620 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from X_linked intellectual disability; XLID to X-linked intellectual disability, MONDO:0100284
Intellectual disability v3.1619 WNK3 Arina Puzriakova Classified gene: WNK3 as Amber List (moderate evidence)
Intellectual disability v3.1619 WNK3 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families, all presenting with ID in association with variants in the WNK3 gene.
Intellectual disability v3.1619 WNK3 Arina Puzriakova Gene: wnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1618 WNK3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: WNK3.
Intellectual disability v3.1618 WNK3 Arina Puzriakova reviewed gene: WNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 35678782; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, childhood onset v1.237 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Dystonia, chorea or related movement disorder, adult onset v1.170 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Intellectual disability v3.1618 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Early onset or syndromic epilepsy v2.542 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
DDG2P v2.76 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Fetal anomalies v1.871 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Likely inborn error of metabolism v2.259 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Undiagnosed metabolic disorders v1.538 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Neurodegenerative disorders, adult onset v2.275 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Iron metabolism disorders - NOT common HFE mutations v1.33 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Bleeding and platelet disorders v1.42 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Arthrogryposis v3.159 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Haematological malignancies cancer susceptibility v2.33 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Inherited bleeding disorders v1.172 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Lysosomal storage disorder v1.78 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Cholestasis v1.110 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Familial pulmonary fibrosis v1.29 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Parkinson Disease and Complex Parkinsonism v1.108 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Fetal hydrops v1.55 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Neonatal cholestasis v1.24 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Haematological malignancies for rare disease v1.12 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1..
Structural eye disease v1.132 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Intellectual disability v3.1618 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Early onset or syndromic epilepsy v2.542 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
DDG2P v2.76 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Fetal anomalies v1.871 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Arthrogryposis v3.159 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Bilateral congenital or childhood onset cataracts v2.109 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Hydrocephalus v2.129 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Dystonia, chorea or related movement disorder, childhood onset v1.237 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Intellectual disability v3.1618 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
DDG2P v2.76 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Fetal anomalies v1.871 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Likely inborn error of metabolism v2.259 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Undiagnosed metabolic disorders v1.538 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Intestinal failure or congenital diarrhoea v1.48 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
COVID-19 research v1.129 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Gastrointestinal epithelial barrier disorders v1.73 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Dystonia, chorea or related movement disorder, childhood onset v1.237 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Intellectual disability v3.1618 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
DDG2P v2.76 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Fetal anomalies v1.871 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Likely inborn error of metabolism v2.259 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Undiagnosed metabolic disorders v1.538 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Intestinal failure or congenital diarrhoea v1.48 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
COVID-19 research v1.129 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Gastrointestinal epithelial barrier disorders v1.73 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Dystonia, chorea or related movement disorder, childhood onset v1.237 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Intellectual disability v3.1618 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
DDG2P v2.76 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Fetal anomalies v1.871 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Likely inborn error of metabolism v2.259 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Undiagnosed metabolic disorders v1.538 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Intestinal failure or congenital diarrhoea v1.48 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
COVID-19 research v1.129 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Gastrointestinal epithelial barrier disorders v1.73 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Dystonia, chorea or related movement disorder, childhood onset v1.237 TTC37 Sarah Leigh commented on gene: TTC37
Intellectual disability v3.1618 TTC37 Sarah Leigh commented on gene: TTC37
DDG2P v2.76 TTC37 Sarah Leigh commented on gene: TTC37
Fetal anomalies v1.871 TTC37 Sarah Leigh commented on gene: TTC37
Likely inborn error of metabolism v2.259 TTC37 Sarah Leigh commented on gene: TTC37: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.
Undiagnosed metabolic disorders v1.538 TTC37 Sarah Leigh commented on gene: TTC37: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 TTC37 Sarah Leigh commented on gene: TTC37
Intestinal failure or congenital diarrhoea v1.48 TTC37 Sarah Leigh edited their review of gene: TTC37: Added comment: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; Changed publications to: 27302973
COVID-19 research v1.129 TTC37 Sarah Leigh commented on gene: TTC37
Gastrointestinal epithelial barrier disorders v1.73 TTC37 Sarah Leigh edited their review of gene: TTC37: Added comment: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; Changed publications to: 27302973
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 TTC37 Sarah Leigh edited their review of gene: TTC37: Added comment: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; Changed publications to: 27302973
Dystonia, chorea or related movement disorder, childhood onset v1.237 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Intellectual disability v3.1618 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
DDG2P v2.76 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Fetal anomalies v1.871 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Likely inborn error of metabolism v2.259 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Undiagnosed metabolic disorders v1.538 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 SKIV2L Sarah Leigh commented on gene: SKIV2L
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Intestinal failure or congenital diarrhoea v1.48 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
COVID-19 research v1.129 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Gastrointestinal epithelial barrier disorders v1.73 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Dystonia, chorea or related movement disorder, childhood onset v1.237 SKIV2L Sarah Leigh commented on gene: SKIV2L
Intellectual disability v3.1618 SKIV2L Sarah Leigh commented on gene: SKIV2L: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.
DDG2P v2.76 SKIV2L Sarah Leigh commented on gene: SKIV2L
Fetal anomalies v1.871 SKIV2L Sarah Leigh commented on gene: SKIV2L
Likely inborn error of metabolism v2.259 SKIV2L Sarah Leigh commented on gene: SKIV2L: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.
Undiagnosed metabolic disorders v1.538 SKIV2L Sarah Leigh commented on gene: SKIV2L: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.
Intestinal failure or congenital diarrhoea v1.48 SKIV2L Sarah Leigh edited their review of gene: SKIV2L: Added comment: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; Changed publications to: 27302973, 22444670
COVID-19 research v1.129 SKIV2L Sarah Leigh commented on gene: SKIV2L
Gastrointestinal epithelial barrier disorders v1.73 SKIV2L Sarah Leigh edited their review of gene: SKIV2L: Added comment: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; Changed publications to: 27302973, 22444670
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 SKIV2L Sarah Leigh edited their review of gene: SKIV2L: Added comment: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; Changed publications to: 27302973, 22444670
Structural eye disease v1.132 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Intellectual disability v3.1618 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Early onset or syndromic epilepsy v2.542 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
DDG2P v2.76 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Fetal anomalies v1.871 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Arthrogryposis v3.159 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Bilateral congenital or childhood onset cataracts v2.109 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Hydrocephalus v2.129 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Structural eye disease v1.132 KIAA1109 Sarah Leigh commented on gene: KIAA1109
Intellectual disability v3.1618 KIAA1109 Sarah Leigh edited their review of gene: KIAA1109: Added comment: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; Changed phenotypes to: Alkuraya-Kucinskas syndrome 617822
Early onset or syndromic epilepsy v2.542 KIAA1109 Sarah Leigh commented on gene: KIAA1109: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.
DDG2P v2.76 KIAA1109 Sarah Leigh commented on gene: KIAA1109
Fetal anomalies v1.871 KIAA1109 Sarah Leigh commented on gene: KIAA1109
Arthrogryposis v3.159 KIAA1109 Sarah Leigh edited their review of gene: KIAA1109: Added comment: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; Changed phenotypes to: Alkuraya-Kucinskas syndrome 617822
Bilateral congenital or childhood onset cataracts v2.109 KIAA1109 Sarah Leigh commented on gene: KIAA1109
Hydrocephalus v2.129 KIAA1109 Sarah Leigh edited their review of gene: KIAA1109: Added comment: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; Changed phenotypes to: Alkuraya-Kucinskas syndrome 617822
Likely inborn error of metabolism v2.259 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Dystonia, chorea or related movement disorder, childhood onset v1.237 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Dystonia, chorea or related movement disorder, adult onset v1.170 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Intellectual disability v3.1618 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Early onset or syndromic epilepsy v2.542 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
DDG2P v2.76 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Fetal anomalies v1.871 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Undiagnosed metabolic disorders v1.538 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Neurodegenerative disorders, adult onset v2.275 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Iron metabolism disorders - NOT common HFE mutations v1.33 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Bleeding and platelet disorders v1.42 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Arthrogryposis v3.159 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Haematological malignancies cancer susceptibility v2.33 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Inherited bleeding disorders v1.172 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Lysosomal storage disorder v1.78 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Cholestasis v1.110 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Familial pulmonary fibrosis v1.29 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Parkinson Disease and Complex Parkinsonism v1.108 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Dystonia, chorea or related movement disorder, childhood onset v1.237 GBA Sarah Leigh commented on gene: GBA
Dystonia, chorea or related movement disorder, adult onset v1.170 GBA Sarah Leigh commented on gene: GBA: The new_gene_name tag has been added. The new name for GBA is GBA1.
Intellectual disability v3.1618 GBA Sarah Leigh commented on gene: GBA
Early onset or syndromic epilepsy v2.542 GBA Sarah Leigh commented on gene: GBA
DDG2P v2.76 GBA Sarah Leigh commented on gene: GBA
Fetal anomalies v1.871 GBA Sarah Leigh commented on gene: GBA
Likely inborn error of metabolism v2.259 GBA Sarah Leigh commented on gene: GBA
Undiagnosed metabolic disorders v1.538 GBA Sarah Leigh commented on gene: GBA
Neurodegenerative disorders, adult onset v2.275 GBA Sarah Leigh commented on gene: GBA
Iron metabolism disorders - NOT common HFE mutations v1.33 GBA Sarah Leigh commented on gene: GBA
Bleeding and platelet disorders v1.42 GBA Sarah Leigh commented on gene: GBA
Arthrogryposis v3.159 GBA Sarah Leigh commented on gene: GBA
Haematological malignancies cancer susceptibility v2.33 GBA Sarah Leigh commented on gene: GBA
Inherited bleeding disorders v1.172 GBA Sarah Leigh commented on gene: GBA
Lysosomal storage disorder v1.78 GBA Sarah Leigh commented on gene: GBA
Cholestasis v1.110 GBA Sarah Leigh commented on gene: GBA
Familial pulmonary fibrosis v1.29 GBA Sarah Leigh commented on gene: GBA
Parkinson Disease and Complex Parkinsonism v1.108 GBA Sarah Leigh commented on gene: GBA
Fetal hydrops v1.55 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Fetal hydrops v1.55 GBA Sarah Leigh commented on gene: GBA
Haematological malignancies for rare disease v1.12 GBA Sarah Leigh commented on gene: GBA
Neonatal cholestasis v1.24 GBA Sarah Leigh commented on gene: GBA: The new_gene_name tag has been added. The new name for GBA is GBA1.
Neonatal cholestasis v1.24 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Haematological malignancies for rare disease v1.12 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Pulmonary arterial hypertension v2.22 ATP13A3 Sarah Leigh Phenotypes for gene: ATP13A3 were changed from Heritable pulmonary arterial hypertension; HPAH to Pulmonary hypertension, primary, 5, OMIM:265400; pulmonary hypertension, primary, autosomal recessive, MONDO:0009935
Pulmonary arterial hypertension v2.21 ATP13A3 Sarah Leigh Tag gene-checked was removed from gene: ATP13A3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 SASH3 Sarah Leigh Phenotypes for gene: SASH3 were changed from Combined immunodeficiency; lymphopenia; neutropenia; immunodysregulation; autoimmune cytopenias to Immunodeficiency 102, OMIM:301082
Primary immunodeficiency or monogenic inflammatory bowel disease v2.556 OAS1 Sarah Leigh Phenotypes for gene: OAS1 were changed from Autoinflammatory Disorders; Pulmonary alveolar proteinosis; Recurrent fever; Dermatitis; Inflammatory bowel disease; Hypogammaglobulinemia to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia, OMIM:618042
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 OAS1 Sarah Leigh Tag gene-checked was removed from gene: OAS1.
COVID-19 research v1.129 OAS1 Sarah Leigh Phenotypes for gene: OAS1 were changed from OAS1 GOF; Autoinflammatory Disorders; Pulmonary alveolar proteinosis, skin rash to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia, OMIM:618042
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 DNASE2 Sarah Leigh Tag gene-checked was removed from gene: DNASE2.
COVID-19 research v1.128 DNASE2 Sarah Leigh Tag gene-checked was removed from gene: DNASE2.
Severe microcephaly v2.306 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental abnormality HP:0012759 to Neurodevelopmental disorder with poor growth and skeletal anomalies, OMIM:619880
Intellectual disability v3.1618 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental abnormality HP:0012759 to Neurodevelopmental disorder with poor growth and skeletal anomalies, OMIM:619880
Intellectual disability v3.1617 PCDHGC4 Sarah Leigh Tag gene-checked was removed from gene: PCDHGC4.
Early onset or syndromic epilepsy v2.542 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental abnormality HP:0012759 to Neurodevelopmental disorder with poor growth and skeletal anomalies, OMIM:619880
Early onset or syndromic epilepsy v2.541 PCDHGC4 Sarah Leigh Tag gene-checked was removed from gene: PCDHGC4.
Severe microcephaly v2.305 PCDHGC4 Sarah Leigh Tag gene-checked was removed from gene: PCDHGC4.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.76 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Parenti-Mignot neurodevelopmental syndrome, OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1617 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Parenti-Mignot neurodevelopmental syndrome, OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v2.541 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1616 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1615 CHD5 Sarah Leigh Tag gene-checked was removed from gene: CHD5.
Intellectual disability v3.1615 NR4A2 Sarah Leigh Phenotypes for gene: NR4A2 were changed from Language impairment; Intellectual disability; Autism; Behavioral abnormality; No OMIM number to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911
Intellectual disability v3.1614 NR4A2 Sarah Leigh Tag gene-checked was removed from gene: NR4A2.
Early onset or syndromic epilepsy v2.540 NR4A2 Sarah Leigh Phenotypes for gene: NR4A2 were changed from Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911
Early onset or syndromic epilepsy v2.539 NR4A2 Sarah Leigh Tag gene-checked was removed from gene: NR4A2.
Neurodegenerative disorders, adult onset v2.275 NR4A2 Sarah Leigh Phenotypes for gene: NR4A2 were changed from Parkinson Disease, Dominant/Recessive (susceptibility to) to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911
DDG2P v2.76 GNAI1 Sarah Leigh Tag gene-checked was removed from gene: GNAI1.
Intellectual disability v3.1614 GNAI1 Sarah Leigh Tag gene-checked was removed from gene: GNAI1.
Bilateral congenital or childhood onset cataracts v2.109 ZNF526 Sarah Leigh Tag gene-checked was removed from gene: ZNF526.
Severe microcephaly v2.305 ZNF526 Sarah Leigh Tag gene-checked was removed from gene: ZNF526.
Intellectual disability v3.1614 ZNF526 Sarah Leigh Tag gene-checked was removed from gene: ZNF526.
DDG2P v2.76 ZNF526 Sarah Leigh Phenotypes for gene: ZNF526 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Dentici-Novelli neurodevelopmental syndrome, OMIM:619877
Bilateral congenital or childhood onset cataracts v2.109 ZNF526 Sarah Leigh Phenotypes for gene: ZNF526 were changed from Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia to Dentici-Novelli neurodevelopmental syndrome, OMIM:619877
Haematological malignancies for rare disease v1.12 RPS15 Dmitrijs Rots reviewed gene: RPS15: Rating: RED; Mode of pathogenicity: None; Publications: PMID:28297620, 19061985; Phenotypes: ; Mode of inheritance: None
Inherited predisposition to acute myeloid leukaemia (AML) v1.21 MBD4 Claire Palles gene: MBD4 was added
gene: MBD4 was added to Inherited predisposition to acute myeloid leukaemia (AML). Sources: Literature
Mode of inheritance for gene: MBD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBD4 were set to 35460607
Phenotypes for gene: MBD4 were set to polyposis; CRC; AML; MDS; UVM
Penetrance for gene: MBD4 were set to Complete
Review for gene: MBD4 was set to GREEN
Added comment: Bi-allelic carriers are at a high increased risk of colorectal polyposis, MDS/AML and uveal melanoma. Mono-allelic carriers are not at an increased risk of AML or polyposis in the data we have so far.
Sources: Literature
GI tract tumours v1.19 MBD4 Claire Palles gene: MBD4 was added
gene: MBD4 was added to GI tract tumours. Sources: Literature
Mode of inheritance for gene: MBD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBD4 were set to 35460607
Phenotypes for gene: MBD4 were set to polyposis; CRC; AML; MDS; UVM
Penetrance for gene: MBD4 were set to Complete
Review for gene: MBD4 was set to GREEN
Added comment: Bi-allelic loss of function mutation carriers at high risk of early onset AML, colorectal polyposis an uveal melanoma. Heterozygous monoallelic carriers at no significantly increased risk in data so far.
Sources: Literature
Early onset or syndromic epilepsy v2.539 ATP6V0A1 Sarah Leigh Tag Q3_22_NHS_review was removed from gene: ATP6V0A1.
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh edited their review of gene: ATP6V0A1: Added comment: None of the biallelic cases reported by PMID: 34909687, exhibited microcephaly as a result of this, biallelic mode of inheritance has not been included for ATP6V0A1 on the Severe microcephaly panel.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Tag Q3_22_NHS_review was removed from gene: ATP6V0A1.
Ataxia and cerebellar anomalies - childhood onset v2.296 ATP6V0A1 Sarah Leigh Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Tag Q3_22_NHS_review was removed from gene: ATP6V0A1.
Ataxia and cerebellar anomalies - childhood onset v2.296 ATP6V0A1 Sarah Leigh edited their review of gene: ATP6V0A1: Added comment: Only 2/4 biallelic cases reported by PMID: 34909687, exhibited ataxia, as a result of this biallelic mode of inheritance has not been included for ATP6V0A1 on the Ataxia and cerebellar anomalies - narrow panel.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v2.296 ATP6V0A1 Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.539
Ataxia and cerebellar anomalies - childhood onset v2.296 ATP6V0A1 Sarah Leigh gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: ATP6V0A1.
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687; 33833240
Phenotypes for gene: ATP6V0A1 were set to ATP6V0A1-related developmental disorder (monoallelic)
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.539
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: ATP6V0A1.
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687; 33833240
Phenotypes for gene: ATP6V0A1 were set to ATP6V0A1-related developmental disorder (monoallelic)
Fetal anomalies v1.871 ARHGAP29 Eleanor Williams Publications for gene: ARHGAP29 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.237 HNRNPH1 Eleanor Williams Tag gene-checked tag was added to gene: HNRNPH1.
DDG2P v2.75 SRY Eleanor Williams commented on gene: SRY
Fetal anomalies v1.870 SRY Eleanor Williams commented on gene: SRY: Added Y chromosome tag to indicate this gene is encoded on the Y chromosome, which is currently not included in the Bioinformatics tiering pipeline.
Fetal anomalies v1.870 SRY Eleanor Williams Tag y-chromosome tag was added to gene: SRY.
DDG2P v2.75 SRY Eleanor Williams Tag y-chromosome tag was added to gene: SRY.
Monogenic hearing loss v2.246 GSTT1 Eleanor Williams Tag ensembl_ids_known_missing tag was added to gene: GSTT1.
Monogenic hearing loss v2.246 GSTT1 Eleanor Williams commented on gene: GSTT1
Early onset or syndromic epilepsy v2.539 ATP6V0A1 Sarah Leigh Entity copied from Intellectual disability v3.1614
Early onset or syndromic epilepsy v2.539 ATP6V0A1 Sarah Leigh gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: ATP6V0A1.
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687; 33833240
Phenotypes for gene: ATP6V0A1 were set to ATP6V0A1-related developmental disorder (monoallelic)
Intellectual disability v3.1614 ATP6V0A1 Sarah Leigh Added comment: Comment on phenotypes: Phenotype from Gen2Phen https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4422
Intellectual disability v3.1614 ATP6V0A1 Sarah Leigh Phenotypes for gene: ATP6V0A1 were changed from ATP6V0A1-related developmental disorder (monoallelic) to ATP6V0A1-related developmental disorder (monoallelic)
Intellectual disability v3.1613 ATP6V0A1 Sarah Leigh Phenotypes for gene: ATP6V0A1 were changed from Developmental disorder; Rett syndrome-like to ATP6V0A1-related developmental disorder (monoallelic)
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: ATP6V0A1.
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh edited their review of gene: ATP6V0A1: Added comment: Not associated with a phenotype in OMIM, but as definitive Gen2Phen gene for ATP6V0A1-related developmental disorder (monoallelic). At least four variants have been reported as de novo heterozygous variants in 14 apparently unrelated cases, with intellectual disability (11/11 cases who could be assessed), epilepsy/EEG abnormalities (11/13 who could be assessed), microcephaly (6/12 cases who could be assessed), ataxia (6/13 cases who could be assessed) and various other phenotypic features (PMID: 34909687 (table 1) & 33833240). Six additional ATP6V0A1 variants were reported as biallelic in four apparently unrelated cases, who all had intellectual disability, epilepsy/EEG abnormalities plus cerebral and cerebellar atrophy / brain atrophy (PMID: 34909687 (table 1) & 33833240).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh changed review comment from: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.; to: Comment on mode of inheritance: Monoallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene.
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh changed review comment from: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.; to: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh Added comment: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh Mode of inheritance for gene: ATP6V0A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1610 ATP6V0A1 Sarah Leigh Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Intellectual disability v3.1610 ATP6V0A1 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 v3.1610 ATP6V0A1 Sarah Leigh Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1609 ATP6V0A1 Sarah Leigh Tag Q3_22_rating tag was added to gene: ATP6V0A1.
Tag Q3_22_NHS_review tag was added to gene: ATP6V0A1.
Intellectual disability v3.1609 ATP6V0A1 Sarah Leigh Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Intellectual disability v3.1608 TMEM63C Sarah Leigh Classified gene: TMEM63C as Amber List (moderate evidence)
Intellectual disability v3.1608 TMEM63C Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, as mild intellectual disability has been diagnosed in the three families carrying TMEM63C variants reported in PMID: 35718349.
Intellectual disability v3.1608 TMEM63C Sarah Leigh Gene: tmem63c has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.139 TMEM63C Sarah Leigh Classified gene: TMEM63C as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.139 TMEM63C Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary spastic paraplegia, childhood onset v2.139 TMEM63C Sarah Leigh Gene: tmem63c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1607 TMEM63C Sarah Leigh gene: TMEM63C was added
gene: TMEM63C was added to Intellectual disability. Sources: Literature
Q3_22_rating tags were added to gene: TMEM63C.
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to 35718349
Phenotypes for gene: TMEM63C were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: TMEM63C was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID:35718349 reports four TMEM63C variants in seven individuals from three unrelated families with childhood onset hereditary spastic paraplegia, with mild intellectual disability in some cases. Functional studies in PMID:35718349, reveal a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.138 TMEM63C Sarah Leigh gene: TMEM63C was added
gene: TMEM63C was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q3_22_rating tags were added to gene: TMEM63C.
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to 35718349
Phenotypes for gene: TMEM63C were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: TMEM63C was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID:35718349 reports four TMEM63C variants in seven individuals from three unrelated families with childhood onset hereditary spastic paraplegia, with mild intellectual disability in some cases. Functional studies in PMID:35718349, reveal a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies.
Sources: Literature
Severe microcephaly v2.304 TUBG1 Gavin Ryan gene: TUBG1 was added
gene: TUBG1 was added to Severe microcephaly. Sources: NHS GMS
Mode of inheritance for gene: TUBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBG1 were set to 23603762; 31151415
Penetrance for gene: TUBG1 were set to unknown
Mode of pathogenicity for gene: TUBG1 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: TUBG1 was set to GREEN
Added comment: Variant has been reported in number of individuals presenting with microcephaly by Poirier et al 2013, and Yuen et al 2019. All reported variants are missense. Identified individuals through GMS presenting with microcephaly prenatally who have pathogenic variants in this gene identified postnatally. Gene now present on fetal anomalies panel.
Sources: NHS GMS
Intellectual disability v3.1606 ATP6V0A1 Mike Spiller changed review comment from: Bott et al 2021 PMID: 34909687

17 individuals from 14 unrelated families

12 individuals with de novo variants in ATP6V0A1.
Associated with severe intellectual disability and refractory seizures following initial normal development.
1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some.
Dysmorphic features less common.

7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q.

Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp).
Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies.

Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function.
Supported by data showing impaired maturation of Cathepsin D (requires acidic pH).
Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980).

Strong evidence that pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance.
Recommend upgrade to Green for ID and epilepsy.; to: Bott et al 2021 PMID: 34909687

17 individuals from 14 unrelated families

12 individuals with de novo variants in ATP6V0A1.
Associated with severe intellectual disability and refractory seizures following initial normal development.
1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some.
Dysmorphic features less common.

7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q.

Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp).
Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies.

Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function.
Supported by data showing impaired maturation of Cathepsin D (requires acidic pH).
Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980).

Strong evidence that heterozygous pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance.
Recommend upgrade to Green for ID and epilepsy.
Intellectual disability v3.1606 ATP6V0A1 Mike Spiller reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34909687; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sarcoma susceptibility v1.72 FANCC Arina Puzriakova Tag Q3_22_expert_review tag was added to gene: FANCC.
Sarcoma susceptibility v1.72 FANCC Arina Puzriakova Publications for gene: FANCC were set to PMID: 35512711
Sarcoma susceptibility v1.71 FANCC Arina Puzriakova Classified gene: FANCC as Amber List (moderate evidence)
Sarcoma susceptibility v1.71 FANCC Arina Puzriakova Added comment: Comment on list classification: Rating Amber but will flag this gene for GMS review to determine whether there is enough evidence supporting contribution of germline variants in FANCC to sarcoma pathogenesis.

Gillani et al., (2022) reported statistically significant enrichment for predicted pathogenic germline variants in the FANCC gene in a cohort of European Ewing sarcoma patients. However, variants have reduced penetrance and the overall frequency of these variants was low (1.5% in discovery cohort, 0.8% in validation cohort).
Chan etl al., (2017) also identified another likely pathogenic frameshift deletion in FANCC in an individual with epitheloid sarcoma
Sarcoma susceptibility v1.71 FANCC Arina Puzriakova Gene: fancc has been classified as Amber List (Moderate Evidence).
Sarcoma susceptibility v1.70 FANCC Arina Puzriakova Phenotypes for gene: FANCC were changed from Ewing Sarcome to Ewing sarcoma, MONDO:0012817
Dystonia, chorea or related movement disorder, childhood onset v1.237 VPS4A Arina Puzriakova Tag watchlist_moi tag was added to gene: VPS4A.
Dystonia, chorea or related movement disorder, childhood onset v1.237 VPS4A Arina Puzriakova changed review comment from: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.; to: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date. Added 'watchlist_moi tag to allow monitoring for additional cases.
Intellectual disability v3.1606 HIST1H4J Arina Puzriakova Tag watchlist tag was added to gene: HIST1H4J.
Intellectual disability v3.1606 HIST1H4J Arina Puzriakova Phenotypes for gene: HIST1H4J were changed from microcephaly; intellectual disability; dysmorphic features to ?Tessadori-van Haaften neurodevelopmental syndrome 2 , OMIM:619759
Intellectual disability v3.1605 HIST1H4J Arina Puzriakova Publications for gene: HIST1H4J were set to 31804630; 35202563
Intellectual disability v3.1605 HIST1H4J Arina Puzriakova Publications for gene: HIST1H4J were set to 31804630
Severe microcephaly v2.304 HIST1H4C Arina Puzriakova Mode of pathogenicity for gene: HIST1H4C 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
Severe microcephaly v2.303 HIST1H4C Arina Puzriakova Publications for gene: HIST1H4C were set to 28920961
Severe microcephaly v2.302 HIST1H4C Arina Puzriakova Phenotypes for gene: HIST1H4C were changed from Growth delay, microcephaly and intellectual disability to Tessadori-van Haaften neurodevelopmental syndrome 1, OMIM:61975
Retinal disorders v2.276 C2 Arina Puzriakova Phenotypes for gene: C2 were changed from Macular Degeneration to {Macular degeneration, age-related, 14, reduced risk of}, OMIM:615489
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh changed review comment from: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature; to: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants. Decipher also reports four cases with seizures carrying ASH1L variants.
Sources: Literature
Congenital myopathy v2.83 HACD1 Tracy Lester reviewed gene: HACD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15829503, 23933735, 32426512, 33354762; Phenotypes: Hypotonia, muscle weakness, motor delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh changed review comment from: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature; to: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Tag Q3_22_rating tag was added to gene: ASH1L.
Tag Q3_22_expert_review tag was added to gene: ASH1L.
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Classified gene: ASH1L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Added comment: Comment on list classification: The opinion of a GMS expert is required, to decide whether or not this gene can be rated as green on the Genetic epilepsy syndromes panel
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Gene: ash1l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.537 ASH1L Sarah Leigh changed review comment from: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 & 25961944 have reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature; to: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature
Early onset or syndromic epilepsy v2.537 ASH1L Sarah Leigh gene: ASH1L was added
gene: ASH1L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ASH1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASH1L were set to 34373061; 25961944
Phenotypes for gene: ASH1L were set to Intellectual developmental disorder, autosomal dominant 52, OMIM:617796
Review for gene: ASH1L was set to AMBER
Added comment: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 & 25961944 have reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature
Intellectual disability v3.1604 SYNE2 Sarah Leigh gene: SYNE2 was added
gene: SYNE2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SYNE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYNE2 were set to 34573277
Phenotypes for gene: SYNE2 were set to autism spectrum disorder, developmental delay and intellectual disability
Review for gene: SYNE2 was set to RED
Added comment: Biallelic SYNE2 variants are not associated with autism spectrum disorder, developmental delay and intellectual disability in OMIM or Gen2Phen. PMID: 34573277 reports compound heterozygous SYNE2 variants in a child with autism spectrum disorder, developmental delay and intellectual disability, together with supportive functional studies.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.41 SYNE2 Sarah Leigh Phenotypes for gene: SYNE2 were changed from Emery-Dreifuss muscular dystrophy 5, autosomal dominant 612999; congenital muscular dystrophy to Emery-Dreifuss muscular dystrophy 5, autosomal dominant, OMIM:612999
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.40 SYNE2 Sarah Leigh Added comment: Comment on publications: PMID: 19542096 refers only to variants in SYNE1 and so is not relevant to SYNE2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.40 SYNE2 Sarah Leigh Publications for gene: SYNE2 were set to 17761684; 19542096; 20301609
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.39 SYNE2 Sarah Leigh Publications for gene: SYNE2 were set to 17761684; 19542096
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 CFHR5 Dmitrijs Rots reviewed gene: CFHR5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 CFHR4 Dmitrijs Rots reviewed gene: CFHR4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 CFHR1 Dmitrijs Rots reviewed gene: CFHR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 CFHR3 Dmitrijs Rots reviewed gene: CFHR3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.237 CACNB4 Eleanor Williams Tag for-review was removed from gene: CACNB4.
Dystonia, chorea or related movement disorder, childhood onset v1.237 COL6A3 Eleanor Williams Tag for-review was removed from gene: COL6A3.
Dystonia, chorea or related movement disorder, childhood onset v1.237 YIF1B Eleanor Williams Tag for-review was removed from gene: YIF1B.
Dystonia, chorea or related movement disorder, childhood onset v1.237 HNRNPH1 Eleanor Williams Tag for-review was removed from gene: HNRNPH1.
Dystonia, chorea or related movement disorder, childhood onset v1.237 EIF2AK2 Eleanor Williams Tag for-review was removed from gene: EIF2AK2.
Dystonia, chorea or related movement disorder, childhood onset v1.237 NDUFA2 Eleanor Williams Tag for-review was removed from gene: NDUFA2.
Dystonia, chorea or related movement disorder, childhood onset v1.237 RNU7-1 Eleanor Williams Tag for-review was removed from gene: RNU7-1.
Dystonia, chorea or related movement disorder, childhood onset v1.237 VPS4A Eleanor Williams Tag for-review was removed from gene: VPS4A.
Tag Q2_22_rating was removed from gene: VPS4A.
Dystonia, chorea or related movement disorder, childhood onset v1.237 CACNB4 Sarah Leigh commented on gene: CACNB4: NHSGenomic Medicine Service consideration - limited evidence for biallelic mode of inheritance.
Dystonia, chorea or related movement disorder, childhood onset v1.237 CACNB4 Sarah Leigh commented on gene: CACNB4: After NHSGenomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Dystonia, chorea or related movement disorder, childhood onset v1.237 COL6A3 Sarah Leigh commented on gene: COL6A3
Dystonia, chorea or related movement disorder, childhood onset v1.237 YIF1B Sarah Leigh commented on gene: YIF1B
Dystonia, chorea or related movement disorder, childhood onset v1.237 HNRNPH1 Sarah Leigh commented on gene: HNRNPH1
Dystonia, chorea or related movement disorder, childhood onset v1.237 EIF2AK2 Sarah Leigh commented on gene: EIF2AK2
Dystonia, chorea or related movement disorder, childhood onset v1.237 NDUFA2 Sarah Leigh commented on gene: NDUFA2
Dystonia, chorea or related movement disorder, childhood onset v1.237 RNU7-1 Sarah Leigh commented on gene: RNU7-1
Dystonia, chorea or related movement disorder, childhood onset v1.237 VPS4A Sarah Leigh commented on gene: VPS4A
Dystonia, chorea or related movement disorder, childhood onset v1.236 COL6A3 Eleanor Williams Source Expert Review Amber was added to COL6A3.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.236 YIF1B Eleanor Williams Source Expert Review Green was added to YIF1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.236 HNRNPH1 Eleanor Williams Source Expert Review Green was added to HNRNPH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.236 EIF2AK2 Eleanor Williams Source Expert Review Green was added to EIF2AK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.236 NDUFA2 Eleanor Williams Source Expert Review Green was added to NDUFA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.236 RNU7-1 Eleanor Williams Source Expert Review Green was added to RNU7-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.236 VPS4A Eleanor Williams Source Expert Review Green was added to VPS4A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
DDG2P v2.75 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from TIMOTHY SYNDROME 601005 to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; CACNA1C-related disorder
Long QT syndrome v2.32 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Brugada syndrome 3 (611875); Timothy syndrome (601005) to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Short QT syndrome v2.14 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; Short QT; CACNA1C-related disorder
Short QT syndrome v2.13 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Brugada syndrome 3 611875; syncope; brugada syndrome; scd; Brugada syndrome 3 (611875); short qt; Timothy syndrome (601005) to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Intellectual disability v3.1603 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Brugada syndrome 3 611875; Timothy syndrome 601005 to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Hypertrophic cardiomyopathy v2.40 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Hypertrophic cardiomyopathy; Brugada syndrome 3 611875; Long QT syndrome 8 618447; Timothy syndrome 601005 to Hypertrophic cardiomyopathy; Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Paediatric or syndromic cardiomyopathy v1.75 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from CACNA1C-related disorder to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Fetal anomalies v1.870 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Fetal anomalies v1.869 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from TIMOTHY SYNDROME to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Paediatric or syndromic cardiomyopathy v1.74 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from to CACNA1C-related disorder
Early onset or syndromic epilepsy v2.536 ASXL3 Dmitrijs Rots gene: ASXL3 was added
gene: ASXL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ASXL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830
Phenotypes for gene: ASXL3 were set to Bainbridge-Ropers syndrome
Penetrance for gene: ASXL3 were set to Complete
Review for gene: ASXL3 was set to GREEN
Added comment: In a review by Kuechler et al., seizures were reported in 3/15 cases. Additionally Khan et al., report a case with seizure onset since birth. In a description of novel 45 cases and review of previous 45 (n=90) by Schirwani et al., seizures were reported in 28/77 cases. Enough evidence for green rating also on this panel.
Sources: Literature
DDG2P v2.74 RPGRIP1 Dmitrijs Rots reviewed gene: RPGRIP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
DDG2P v2.74 DSPP Dmitrijs Rots reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.74 BFSP2 Dmitrijs Rots reviewed gene: BFSP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cataract; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.538 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Cholestasis v1.110 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.295 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
White matter disorders and cerebral calcification - childhood onset v1.238 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Fetal hydrops v1.55 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Peroxisomal disorders v1.19 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
White matter disorders and cerebral calcification - childhood onset v1.238 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Amyotrophic lateral sclerosis/motor neuron disease v1.59 SLC52A3 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' as I could not identify evidence supporting relevance of heterozygous variants in disease. This is consistent with the MOI in OMIM/G2P and other PanelApp panels.
Amyotrophic lateral sclerosis/motor neuron disease v1.59 SLC52A3 Arina Puzriakova Mode of inheritance for gene: SLC52A3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.274 SLC52A3 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' as I could not identify evidence supporting relevance of heterozygous variants in disease. This is consistent with the MOI in OMIM/G2P and other PanelApp panels.
Neurodegenerative disorders, adult onset v2.274 SLC52A3 Arina Puzriakova Mode of inheritance for gene: SLC52A3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.259 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease Ic, 232240; Glycogen storage disease Ib, 232220; Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ib and Ic; Glycogen storage disease type 1b, von Gierke (Glycogen storage disorders); heptomgaly, feed intolerance , inflammatory bowel disease, neutropenia to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240; Congenital disorder of glycosylation, type IIw, OMIM:619525
Undiagnosed metabolic disorders v1.538 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease type 1b, von Gierke (Glycogen storage disorders); heptomgaly, feed intolerance , inflammatory bowel disease, neutropenia; Glycogen storage disease Ib, 232220; Glycogen storage disease Ic, 232240; Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ib and Ic to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240; Congenital disorder of glycosylation, type IIw, OMIM:619525
Cytopenia - NOT Fanconi anaemia v1.70 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease Ib, 232220 to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240
COVID-19 research v1.128 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease Ib; Congenital defects of phagocyte number or function; Glycogen storage disease Ib, 232220; Glycogen storage disease type 1b (GS1b); Glycogen storage disease with or without neutropenia; Glycogen storage disease Ic; Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240; Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly; Congenital defects of phagocyte number or function
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease Ic; Glycogen storage disease Ib, 232220; Glycogen storage disease Ib; Glycogen storage disease type 1b (GS1b); Glycogen storage disease with or without neutropenia; Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly; Congenital defects of phagocyte number or function to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240; Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly; Congenital defects of phagocyte number or function
Glycogen storage disease v1.8 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease Ic 232240; Glycogen storage disease Ib 232220 to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240
Gastrointestinal epithelial barrier disorders v1.73 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Early Onset Inflammatory Bowel Disease; Inflammatory Bowel Disease (Very Early Onset); Glycogen storage disease type 1b 232220 to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240; Early Onset Inflammatory Bowel Disease
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease type 1b 232220 to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240
Ketotic hypoglycaemia v1.7 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from heptomgaly, feed intolerance , inflammatory bowel disease, neutropenia; Glycogen storage disease Ib, 232220; Glycogen storage disease Ic, 232240; Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ib and Ic to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240
Likely inborn error of metabolism v2.258 SLC37A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' to the next GMS panel update.

Biallelic LOF variants in this gene cause glycogen storage disorder while monoallelic variants in SLC37A4 are linked to a congenital disorder of glycosylation in OMIM (MIM# 619525) and G2P (definitive disease confidence). Therefore both inheritance patterns are relevant to this panel.
Likely inborn error of metabolism v2.258 SLC37A4 Arina Puzriakova Mode of inheritance for gene: SLC37A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.537 SLC37A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic' to the next GMS panel update.

Biallelic LOF variants in this gene cause glycogen storage disorder while monoallelic variants in SLC37A4 are linked to a congenital disorder of glycosylation in OMIM (MIM# 619525) and G2P (definitive disease confidence). Therefore both inheritance patterns are relevant to this panel.
Undiagnosed metabolic disorders v1.537 SLC37A4 Arina Puzriakova Mode of inheritance for gene: SLC37A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.257 SLC37A4 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SLC37A4.
Congenital disorders of glycosylation v2.85 SLC37A4 Arina Puzriakova Publications for gene: SLC37A4 were set to 32884905
Congenital disorders of glycosylation v2.84 SLC37A4 Arina Puzriakova Classified gene: SLC37A4 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.84 SLC37A4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Monoallelic variants in SLC37A4 are linked to a congenital disorder of glycosylation in OMIM (MIM# 619525) and G2P (definitive disease confidence).

At least 9 individuals from 6 unrelated families have been reported with the same heterozygous variant, c.1267C>T (p.Arg423∗), in SLC37A4. Affected subjects display a metabolic disorder characterised by liver dysfunction, coagulation deficiencies (but no signs of bleeding detected in most), and profound abnormalities in N-glycosylation of serum specific proteins.
Congenital disorders of glycosylation v2.84 SLC37A4 Arina Puzriakova Gene: slc37a4 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v2.83 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Congenital disorder of glycosylation to Congenital disorder of glycosylation, type IIw, OMIM:619525
Congenital disorders of glycosylation v2.82 SLC37A4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SLC37A4.
Retinal disorders v2.275 Eleanor Williams List of related panels changed from Posterior segment abnormalities; Cone Dysfunction Syndrome; Developmental macular and foveal dystrophy; Inherited macular dystrophy; Leber Congenital Amaurosis Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy; Rod Dysfunction Syndrome; Rod-cone dystrophy; Familial exudative vitreoretinopathy; Familial exudative retinopathy; R32; R33; R34; R35; Possible X-linked retinitis pigmentosa; Sorsby retinal dystrophy; Doyne retinal dystrophy to Posterior segment abnormalities; Cone Dysfunction Syndrome; Developmental macular and foveal dystrophy; Inherited macular dystrophy; Leber Congenital Amaurosis Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy; Rod Dysfunction Syndrome; Rod-cone dystrophy; Familial exudative vitreoretinopathy; Familial exudative retinopathy; Sorsby retinal dystrophy; Doyne retinal dystrophy; R32
Intellectual disability v3.1602 ALKBH8 Sarah Leigh Publications for gene: ALKBH8 were set to 31130284; 31079898
Intellectual disability v3.1601 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
Early onset or syndromic epilepsy v2.536 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh edited their review of gene: ZMYM2: Changed rating: AMBER
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 3 variants have been reported in cases with mild to unclassified intellectual disability in PMID: 32891193. The review from Tracy Lester (Genetics laboratory, Oxford UK) mentions several additional de novo variants reported by Decipher associated with intellectual / developmental disability.; to: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 2 variants have been reported in cases with seizures in PMID: 32891193.
CAKUT v1.169 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from CAKUT; Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh Tag Q3_22_rating was removed from gene: ZMYM2.
Tag Q3_22_NHS_review was removed from gene: ZMYM2.
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh Entity copied from Intellectual disability v3.1600
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh gene: ZMYM2 was added
gene: ZMYM2 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_22_rating, Q3_22_NHS_review tags were added to gene: ZMYM2.
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Penetrance for gene: ZMYM2 were set to unknown
Intellectual disability v3.1600 ZMYM2 Sarah Leigh Tag Q3_22_rating tag was added to gene: ZMYM2.
Tag Q3_22_NHS_review tag was added to gene: ZMYM2.
Intellectual disability v3.1600 ZMYM2 Sarah Leigh edited their review of gene: ZMYM2: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 3 variants have been reported in cases with mild to unclassified intellectual disability in PMID: 32891193. The review from Tracy Lester (Genetics laboratory, Oxford UK) mentions several additional de novo variants reported by Decipher associated with intellectual / developmental disability.; Changed rating: GREEN
Intellectual disability v3.1600 ZMYM2 Sarah Leigh Classified gene: ZMYM2 as Amber List (moderate evidence)
Intellectual disability v3.1600 ZMYM2 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 v3.1600 ZMYM2 Sarah Leigh Gene: zmym2 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.38 SYNE2 Tracy Lester reviewed gene: SYNE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301609; Phenotypes: muscular dystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.554 IKBKB Arina Puzriakova Tag Q3_22_MOI tag was added to gene: IKBKB.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.554 IKBKB Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. Both inheritance patterns are associated with a relevant phenotype of primary immunodeficiency, but AR disease is more severe with earlier onset.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.554 IKBKB Arina Puzriakova Mode of inheritance for gene: IKBKB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.553 IKBKB Arina Puzriakova Phenotypes for gene: IKBKB were changed from Immunodeficiency 15, 615592; Combined immunodeficiency; Recurrent bacterial, viral, fungal infections, opportunistic infections; Immunodeficiencies affecting cellular and humoral immunity to Immunodeficiency 15A, OMIM:618204 (AD); Immunodeficiency 15B, OMIM:615592 (AR); Combined immunodeficiency; Recurrent bacterial, viral, fungal infections, opportunistic infections; Immunodeficiencies affecting cellular and humoral immunity
Cystic kidney disease v2.45 IFT140 John Sayer reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: None; Publications: 34890546; Phenotypes: cystic kidney disease, cystic liver disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cystic kidney disease v2.45 GLA John Sayer reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 29770213, 28371803, 27061865, 21290670, 15327390, 15091117; Phenotypes: renal parapelvic cysts, renal cortical cysts; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.168 TMEM260 Eleanor Williams Classified gene: TMEM260 as Green List (high evidence)
CAKUT v1.168 TMEM260 Eleanor Williams Gene: tmem260 has been classified as Green List (High Evidence).
CAKUT v1.167 TMEM260 Eleanor Williams Tag Q4_21_rating was removed from gene: TMEM260.
CAKUT v1.167 TMEM260 Eleanor Williams commented on gene: TMEM260
CAKUT v1.167 ROBO1 Laura Claus gene: ROBO1 was added
gene: ROBO1 was added to CAKUT. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35227688
Phenotypes for gene: ROBO1 were set to unilateral kidney agenesis; bilateral kidney agenesis; vesicoureteral junction obstruction; vesicoureteral reflux; posterior urethral valve; genital malformation; increased kidney echogenicity
Review for gene: ROBO1 was set to GREEN
Added comment: Sources: Literature
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.; to: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) in the Intellectual disabilty panel (https://panelapp.genomicsengland.co.uk/panels/285/gene/CUL3/#!review), all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.
Intellectual disability v3.1599 CUL3 Sarah Leigh Tag Q3_22_rating tag was added to gene: CUL3.
Tag Q3_22_NHS_review tag was added to gene: CUL3.
Intellectual disability v3.1599 CUL3 Sarah Leigh edited their review of gene: CUL3: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh Tag Q3_22_rating tag was added to gene: CUL3.
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh Classified gene: CUL3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.534 CUL3 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 v2.534 CUL3 Sarah Leigh Gene: cul3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.533 CUL3 Sarah Leigh reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1599 CUL3 Sarah Leigh Classified gene: CUL3 as Amber List (moderate evidence)
Intellectual disability v3.1599 CUL3 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 v3.1599 CUL3 Sarah Leigh Gene: cul3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.533 CUL3 Sarah Leigh Publications for gene: CUL3 were set to 32341456
Intellectual disability v3.1598 CUL3 Sarah Leigh Publications for gene: CUL3 were set to 32341456; 25969726; 31696658; 33097317
Early onset or syndromic epilepsy v2.532 CUL3 Sarah Leigh Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496 to Neurodevelopmental disorder with or without autism or seizures, OMIM:619239
Intellectual disability v3.1597 CUL3 Sarah Leigh Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496 to Neurodevelopmental disorder with or without autism or seizures, OMIM:619239
Intellectual disability v3.1596 CUL3 Sarah Leigh Publications for gene: CUL3 were set to 32341456; 25969726
Retinal disorders v2.274 POMT1 Robert Henderson gene: POMT1 was added
gene: POMT1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: POMT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POMT1 were set to PMID:16575835; 31311558; 16887026
Phenotypes for gene: POMT1 were set to retinal detachment
Penetrance for gene: POMT1 were set to unknown
Review for gene: POMT1 was set to GREEN
Added comment: This is currently included on numerous panels but not on the retina/posterior segment panel. It would merit inclusion on an inherited vitreoretinopathy slice.
Sources: Expert list
Intellectual disability v3.1595 CLIC2 Sarah Leigh Publications for gene: CLIC2 were set to 22814392; 25927380
Ovarian cancer pertinent cancer susceptibility v1.11 BRIP1 Sarah Leigh Publications for gene: BRIP1 were set to
Ovarian cancer pertinent cancer susceptibility v1.10 BRIP1 Sarah Leigh Added comment: Comment on phenotypes: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910) {Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419. However, in PMID:31822495 they report very rare BRIP1 missense germline variants (minor allele frequency < 0.0001) in nearly 2% of 2,160 early-onset breast cancer and 1,199 ovarian cancer patients. Functional studies on 20 of these variants revealed 75% resulted in protein hypomorph or null products. The authors also reported that in a clinical cohort of >117,000 breast and ovarian cancer patients, the combined odds ratio associated with BRIP1 hypomorph or null missense carriers compared to the general population was 2.30 (95%CI=1.60-3.30, p<0.0001).
Ovarian cancer pertinent cancer susceptibility v1.10 BRIP1 Sarah Leigh Phenotypes for gene: BRIP1 were changed from {Breast cancer, early-onset, susceptibility to}, OMIM:114480 to familial ovarian cancer, MONDO:0016248
Inherited ovarian cancer (without breast cancer) v2.28 BRIP1 Sarah Leigh changed review comment from: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910)
{Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419; to: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910)
{Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419. However, in PMID:31822495 they report very rare BRIP1 missense germline variants (minor allele frequency < 0.0001) in nearly 2% of 2,160 early-onset breast cancer and 1,199 ovarian cancer patients. Functional studies on 20 of these variants revealed 75% resulted in protein hypomorph or null products. The authors also reported that in a clinical cohort of >117,000 breast and ovarian cancer patients, the combined odds ratio associated with BRIP1 hypomorph or null missense carriers compared to the general population was 2.30 (95%CI=1.60-3.30, p<0.0001).
Inherited ovarian cancer (without breast cancer) v2.28 BRIP1 Sarah Leigh changed review comment from: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910)
{Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419; to: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910)
{Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419
Inherited ovarian cancer (without breast cancer) v2.28 BRIP1 Sarah Leigh Publications for gene: BRIP1 were set to 26315354; 21964575; 29661970
Inherited ovarian cancer (without breast cancer) v2.27 BRIP1 Sarah Leigh Phenotypes for gene: BRIP1 were changed from ovarian epithelial tumor, MONDO:0002229 to familial ovarian cancer, MONDO:0016248
Paediatric disorders - additional genes v1.99 FGF5 Eleanor Williams Classified gene: FGF5 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.99 FGF5 Eleanor Williams Gene: fgf5 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.98 FGF5 Eleanor Williams changed review comment from: This gene was originally added to the DDG2P panel but this gene is not present in the Gene2Phenotype resource. After review by a Genomics England clinician it was decided that this may be the best place for this gene as there is no specific hypertrichosis panel. Rating amber but with a recommendation for green rating if after GMS review it is considered appropriate for this panel.; to: This gene was originally added to the DDG2P panel but this gene is not present in the Developmental Disorders panel in the Gene2Phenotype resource which DDG2P panel reflects.

After review by a Genomics England clinician it was decided that this may be the best place for this gene as there is no specific hypertrichosis panel. Rating amber but with a recommendation for green rating if after GMS review it is considered appropriate for this panel.
Paediatric disorders - additional genes v1.98 FGF5 Eleanor Williams commented on gene: FGF5
Paediatric disorders - additional genes v1.98 FGF5 Eleanor Williams Deleted their review
Paediatric disorders - additional genes v1.98 FGF5 Eleanor Williams Tag Q2_21_NHS_review tag was added to gene: FGF5.
Tag Q2_22_rating tag was added to gene: FGF5.
Tag Q2_22_phenotype tag was added to gene: FGF5.
Tag Q2_22_expert_review tag was added to gene: FGF5.
Paediatric disorders - additional genes v1.98 FGF5 Eleanor Williams Entity copied from DDG2P v2.74
Paediatric disorders - additional genes v1.98 FGF5 Eleanor Williams gene: FGF5 was added
gene: FGF5 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: FGF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF5 were set to PMID: 24989505
Phenotypes for gene: FGF5 were set to Hypertrichosis; long eyelashes
Penetrance for gene: FGF5 were set to Complete
Haematological malignancies cancer susceptibility v2.33 ERCC6L2 Eleanor Williams commented on gene: ERCC6L2
Haematological malignancies cancer susceptibility v2.33 ERCC6L2 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: ERCC6L2.
Tag Q3_22_rating was removed from gene: ERCC6L2.
Tag Q2_22_rating tag was added to gene: ERCC6L2.
Tag Q2_22_NHS_review tag was added to gene: ERCC6L2.
Intellectual disability v3.1594 GLS_GCA Eleanor Williams Tag for-review was removed from STR: GLS_GCA.
Cystic kidney disease v2.45 XPNPEP3 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: XPNPEP3.
Mitochondrial disorders v2.107 XPNPEP3 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: XPNPEP3.
Ataxia and cerebellar anomalies - childhood onset v2.295 TBP_CAG Eleanor Williams Tag for-review was removed from STR: TBP_CAG.
Neurodegenerative disorders, adult onset v2.273 PPP2R2B_CAG Eleanor Williams Tag for-review was removed from STR: PPP2R2B_CAG.
Neurodegenerative disorders, adult onset v2.273 NOP56_GGCCTG Eleanor Williams Tag for-review was removed from STR: NOP56_GGCCTG.
Neurodegenerative disorders, adult onset v2.273 FXN_GAA Eleanor Williams Tag for-review was removed from STR: FXN_GAA.
Neurodegenerative disorders, adult onset v2.273 CSTB_CCCCGCCCCGCG Eleanor Williams Tag for-review was removed from STR: CSTB_CCCCGCCCCGCG.
Neurodegenerative disorders, adult onset v2.273 CACNA1A_CAG Eleanor Williams Tag for-review was removed from STR: CACNA1A_CAG.
Neurodegenerative disorders, adult onset v2.273 ATXN7_CAG Eleanor Williams Tag for-review was removed from STR: ATXN7_CAG.
Neurodegenerative disorders, adult onset v2.273 ATXN3_CAG Eleanor Williams Tag for-review was removed from STR: ATXN3_CAG.
Neurodegenerative disorders, adult onset v2.273 ATXN2_CAG Eleanor Williams Tag for-review was removed from STR: ATXN2_CAG.
Neurodegenerative disorders, adult onset v2.273 ATXN10_ATTCT Eleanor Williams Tag for-review was removed from STR: ATXN10_ATTCT.
Neurodegenerative disorders, adult onset v2.273 ATXN1_CAG Eleanor Williams Tag for-review was removed from STR: ATXN1_CAG.
Likely inborn error of metabolism v2.257 GLS_GCA Eleanor Williams Tag for-review was removed from STR: GLS_GCA.
Hereditary spastic paraplegia, adult onset v1.102 ATXN10_ATTCT Eleanor Williams Tag for-review was removed from STR: ATXN10_ATTCT.
Ataxia and cerebellar anomalies - childhood onset v2.295 PPP2R2B_CAG Eleanor Williams Tag for-review was removed from STR: PPP2R2B_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.295 NOP56_GGCCTG Eleanor Williams Tag for-review was removed from STR: NOP56_GGCCTG.
Ataxia and cerebellar anomalies - childhood onset v2.295 GLS_GCA Eleanor Williams Tag for-review was removed from STR: GLS_GCA.
Ataxia and cerebellar anomalies - childhood onset v2.295 CACNA1A_CAG Eleanor Williams Tag for-review was removed from STR: CACNA1A_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.295 ATXN3_CAG Eleanor Williams Tag for-review was removed from STR: ATXN3_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.295 ATXN10_ATTCT Eleanor Williams Tag for-review was removed from STR: ATXN10_ATTCT.
Ataxia and cerebellar anomalies - childhood onset v2.295 ATXN1_CAG Eleanor Williams Tag for-review was removed from STR: ATXN1_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.295 ATN1_CAG Eleanor Williams Tag for-review was removed from STR: ATN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.170 PPP2R2B_CAG Eleanor Williams Tag for-review was removed from STR: PPP2R2B_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.170 CSTB_CCCCGCCCCGCG Eleanor Williams Tag for-review was removed from STR: CSTB_CCCCGCCCCGCG.
Dystonia, chorea or related movement disorder, adult onset v1.170 CACNA1A_CAG Eleanor Williams Tag for-review was removed from STR: CACNA1A_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.170 ATXN3_CAG Eleanor Williams Tag for-review was removed from STR: ATXN3_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.170 ATXN2_CAG Eleanor Williams Tag for-review was removed from STR: ATXN2_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.170 ATXN1_CAG Eleanor Williams Tag for-review was removed from STR: ATXN1_CAG.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.552 FOXN1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS update. Severe recurrent infections due to T-cell deficiency usually apparent from birth has been associated with both homozygous and heterozygous variants in the FOXN1 gene. Sufficient cases for both inheritance types to rate as Green with this MOI.; to: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS update. Severe recurrent infections due to T-cell deficiency usually apparent from birth have been associated with both homozygous and heterozygous variants in the FOXN1 gene. Sufficient cases for both inheritance types to rate as Green with this MOI.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.552 FOXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS update. Severe recurrent infections due to T-cell deficiency usually apparent from birth has been associated with both homozygous and heterozygous variants in the FOXN1 gene. Sufficient cases for both inheritance types to rate as Green with this MOI.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.552 FOXN1 Arina Puzriakova Mode of inheritance for gene: FOXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.551 FOXN1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: FOXN1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.551 FOXN1 Arina Puzriakova commented on gene: FOXN1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.551 FOXN1 Arina Puzriakova Phenotypes for gene: FOXN1 were changed from T-B+ SCID; T-B+ SCID, congenital alopecia, nail dystrophy, 601705; T-cell immunodeficiency, congenital alopecia, and nail dystrophy; Nude severe combined immunodeficiency; Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect; Combined immunodeficiencies with associated or syndromic features to T-cell immunodeficiency, congenital alopecia, and nail dystrophy, OMIM:601705 (AR); T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, OMIM:618806 (AD); T-B+ SCID; Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect; Combined immunodeficiencies with associated or syndromic features
COVID-19 research v1.127 FOXN1 Arina Puzriakova Phenotypes for gene: FOXN1 were changed from Nude severe combined immunodeficiency; T-cell immunodeficiency, congenital alopecia, and nail dystrophy; T-B+ SCID; Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect; T-B+ SCID, congenital alopecia, nail dystrophy, 601705; Combined immunodeficiencies with associated or syndromic features to T-cell immunodeficiency, congenital alopecia, and nail dystrophy, OMIM:601705 (AR); T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, OMIM:618806 (AD); T-B+ SCID; Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect; Combined immunodeficiencies with associated or syndromic features
Familial cicatricial alopecia v1.5 FOXN1 Arina Puzriakova Phenotypes for gene: FOXN1 were changed from T-cell immunodeficiency, congenital alopecia, and nail dystrophy, 601705; Alopecia and T-Cell Immunodeficiency; congenital severe combined immunodeficiency associated with alopecia to T-cell immunodeficiency, congenital alopecia, and nail dystrophy, OMIM:601705
Paediatric disorders - additional genes v1.97 FOXL2 Catherine Snow changed review comment from: Suitable number of cases with pathogenic variants associated with condition. Gene associated with 2 forms of blepharophimosis/ptosis/epicanthus inversus syndrome. Type 1, eyelid abnormalities are associated with ovarian failure. Type 2 has eyelid abnormalities. As other genes associated with blepharophimosis are not on this panel querying clinical team to see if gene phenotype if suitable for panel.; to: Suitable number of cases with pathogenic variants associated with condition. Gene associated with 2 forms of blepharophimosis/ptosis/epicanthus inversus syndrome. Type 1, eyelid abnormalities are associated with ovarian failure. Type 2 has eyelid abnormalities. As other genes associated with blepharophimosis are not on this panel querying clinical team to see if gene phenotype if suitable for panel.
Following feedback from clinical team this will become Green.
Paediatric disorders - additional genes v1.97 FOXL2 Catherine Snow Tag Q2_22_rating tag was added to gene: FOXL2.
Tag Q2_22_NHS_review tag was added to gene: FOXL2.
Hereditary systemic amyloidosis v1.14 FGA Arina Puzriakova Phenotypes for gene: FGA were changed from Amyloidosis, familial visceral 105200 to Amyloidosis, familial visceral, OMIM:105200
Periodic fever syndromes v1.31 FGA Arina Puzriakova Phenotypes for gene: FGA were changed from Amyloidosis, familial visceral 105200 to Amyloidosis, familial visceral, OMIM:105200
Inherited bleeding disorders v1.172 F13B Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'Monoallelic' to 'Both mono- and biallelic'. Although patients primarily present with biallelic variants, there is also evidence of monoallelic disease albeit in fewer frequency, likely due to the mild extent of symptoms resulting in many carriers going undetected until exposed to trauma.
Inherited bleeding disorders v1.172 F13B Arina Puzriakova Mode of inheritance for gene: F13B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Bleeding and platelet disorders v1.42 F13B Arina Puzriakova Phenotypes for gene: F13B were changed from 613235 Factor XIII deficiency to Factor XIIIB deficiency, OMIM:613235
Inherited bleeding disorders v1.171 F13B Arina Puzriakova Phenotypes for gene: F13B were changed from Factor XIII deficiency; VENOUS THROMBOSIS, SUSCEPTIBILITY TO to Factor XIIIB deficiency, OMIM:613235
Inherited bleeding disorders v1.170 F13A1 Arina Puzriakova Phenotypes for gene: F13A1 were changed from Factor XIII deficiency to Factor XIIIA deficiency, OMIM:613225
Bleeding and platelet disorders v1.41 F13A1 Arina Puzriakova Phenotypes for gene: F13A1 were changed from 613225 Factor XIII deficiency to Factor XIIIA deficiency, OMIM:613225
Haematological malignancies cancer susceptibility v2.33 ERCC6L2 Sarah Leigh Tag Q3_21_NHS_review tag was added to gene: ERCC6L2.
Tag Q3_22_rating tag was added to gene: ERCC6L2.
Haematological malignancies cancer susceptibility v2.33 ERCC6L2 Sarah Leigh Phenotypes for gene: ERCC6L2 were changed from Bone marrow failure syndrome 2, 615715; MDS; AML to Bone marrow failure syndrome 2, OMIM:615715
Haematological malignancies cancer susceptibility v2.32 ERCC6L2 Sarah Leigh Publications for gene: ERCC6L2 were set to PMID: 30936069; PMID: 31221794
Haematological malignancies cancer susceptibility v2.31 ERCC6L2 Sarah Leigh Classified gene: ERCC6L2 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v2.31 ERCC6L2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Haematological malignancies cancer susceptibility v2.31 ERCC6L2 Sarah Leigh Gene: ercc6l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1594 RYR2 Sarah Leigh changed review comment from: PMID: 30170228 reports 34/421 RYR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT1) patients had intellectual disability. It was also possible to establish that de novo variants had arisen in 13/24 of these cases. RYR2 has not been made green on this panel at present, as ID is not a common feature of CPVT1 and it would appear that penetrance is incomplete.; to: PMID: 30170228 reports 34/421 RYR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT1) patients had intellectual disability. It was also possible to establish that de novo RYR2 variants had arisen in 13/24 of these cases. RYR2 has not been made green on this panel at present, as ID is not a common feature of CPVT1 and it would appear that penetrance is incomplete.
Fetal anomalies v1.868 CYP11B1 Arina Puzriakova Added comment: Comment on mode of inheritance: Only biallelic MOI is relevant to this panel, causing Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, OMIM:202010, characterised by androgen excess, virilization, and hypertension (can be detected prenatally by increased levels of tetrahydro-11-deoxycortisol in the amniotic fluid). On the other hand, AD disease arises in the form of familial hyperaldosteronism/hypertension in childhood to early adulthood and therefore should be excluded from the fetal panel.
Fetal anomalies v1.868 CYP11B1 Arina Puzriakova Mode of inheritance for gene: CYP11B1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1594 RYR2 Sarah Leigh reviewed gene: RYR2: Rating: ; Mode of pathogenicity: None; Publications: 30170228; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.867 CYP11B1 Arina Puzriakova Phenotypes for gene: CYP11B1 were changed from Aldosteronism, glucocorticoid-remediable 103900; Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency 202010 to Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, OMIM:202010
Fetal anomalies v1.866 CYP11B1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: CYP11B1.
Intellectual disability v3.1594 RYR2 Sarah Leigh Classified gene: RYR2 as Amber List (moderate evidence)
Intellectual disability v3.1594 RYR2 Sarah Leigh Gene: ryr2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1593 RYR2 Sarah Leigh Tag Q3_22_rating was removed from gene: RYR2.
Tag Q3_22_expert_review was removed from gene: RYR2.
Extreme early-onset hypertension v1.20 CYP11B1 Arina Puzriakova Phenotypes for gene: CYP11B1 were changed from Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, 202010; Aldosteronism, glucocorticoid-remediable, 103900; Early onset hypertension with raised urinary 18-hydroxy-steroids; steroid-sensitive. to Aldosteronism, glucocorticoid-remediable, OMIM:103900; Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, OMIM:202010; Early onset hypertension with raised urinary 18-hydroxy-steroids, steroid-sensitive
Extreme early-onset hypertension v1.19 CYP11B1 Arina Puzriakova Added comment: Comment on mode of inheritance: Familial hyperaldosteronism characterised by hypertension is caused by chimeric fusion of CYP11B1/CYP11B2 (monoallelic to pick this up), while biallelic variants in the CYP11B1 is associated with congenital adrenal hyperplasia which also presents with early-onset moderate to severe hypertension among other features. Therefore updating MOI to 'Both mono- and biallelic'.
Extreme early-onset hypertension v1.19 CYP11B1 Arina Puzriakova Mode of inheritance for gene: CYP11B1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1593 RYR2 Sarah Leigh Tag Q3_22_rating tag was added to gene: RYR2.
Tag Q3_22_expert_review tag was added to gene: RYR2.
Intellectual disability v3.1593 ZMYM2 Tracy Lester reviewed gene: ZMYM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32891193; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Extreme early-onset hypertension v1.18 CYP11B2 Arina Puzriakova Tag chimeric-gene tag was added to gene: CYP11B2.
Extreme early-onset hypertension v1.18 CYP11B1 Arina Puzriakova Tag chimeric-gene tag was added to gene: CYP11B1.
Early onset or syndromic epilepsy v2.531 RYR2 Sarah Leigh edited their review of gene: RYR2: Added comment: PMID: 33897349 reports seven RYR2 variants in five unrelated cases of benign epilepsy of childhood with centrotemporal spikes (BECTS). Three of the affected individuals (cases 1,2 & 3) were heterozygous for a RYR2 variant, in one case (case 2) the variant was de novo and in the remaining cases RYR2 variant had been inherited from an unaffected parent. The remaining two individuals (cases 4 & 5) were compound heterozygous inheriting the RYR2 variants from each parent, who were unaffected apart form the father of case 5, who had arrhythmia.; Changed publications to: 33897349
Differences in sex development v2.62 CYP11B1 Arina Puzriakova Phenotypes for gene: CYP11B1 were changed from Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, 202010 to Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, OMIM:202010; Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
Early onset or syndromic epilepsy v2.531 RYR2 Sarah Leigh Publications for gene: RYR2 were set to 18483626; 29667327; 11208676; 12093772; 11157710
Fetal anomalies v1.866 CYP11A1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: CYP11A1.
Differences in sex development v2.61 CYP11A1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: CYP11A1.
Congenital adrenal hypoplasia v2.11 CYP11A1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: CYP11A1.
Fetal anomalies v1.866 CYP11A1 Arina Puzriakova Publications for gene: CYP11A1 were set to 28425981
Differences in sex development v2.61 CYP11A1 Arina Puzriakova Publications for gene: CYP11A1 were set to 19116240; 18182448
Congenital adrenal hypoplasia v2.11 CYP11A1 Arina Puzriakova Publications for gene: CYP11A1 were set to
Fetal anomalies v1.865 CYP11A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Homozygous, compound heterozygous, and heterozygous (although most rare) variants in the CYP11A1 gene have all been associated with disease. Therefore, MOI should be updated to 'Both mono- and biallelic' at the next GMS panel update.
Fetal anomalies v1.865 CYP11A1 Arina Puzriakova Mode of inheritance for gene: CYP11A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Differences in sex development v2.60 CYP11A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Homozygous, compound heterozygous, and heterozygous (although most rare) variants in the CYP11A1 gene have all been associated with disease. Therefore, MOI should be updated to 'Both mono- and biallelic' at the next GMS panel update.
Differences in sex development v2.60 CYP11A1 Arina Puzriakova Mode of inheritance for gene: CYP11A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v2.10 CYP11A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Homozygous, compound heterozygous, and heterozygous (although most rare) variants in the CYP11A1 gene have all been associated with disease. Therefore, MOI should be updated to 'Both mono- and biallelic' at the next GMS panel update.
Congenital adrenal hypoplasia v2.10 CYP11A1 Arina Puzriakova Mode of inheritance for gene: CYP11A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v2.50 PAX4 Sarah Leigh Publications for gene: PAX4 were set to
Multi-organ autoimmune diabetes v1.11 PAX4 Sarah Leigh Publications for gene: PAX4 were set to
Monogenic diabetes v2.49 KLF11 Sarah Leigh Publications for gene: KLF11 were set to
Multi-organ autoimmune diabetes v1.10 KLF11 Sarah Leigh Publications for gene: KLF11 were set to
Multi-organ autoimmune diabetes v1.9 BLK Sarah Leigh Publications for gene: BLK were set to
Monogenic diabetes v2.48 BLK Sarah Leigh Publications for gene: BLK were set to
Congenital hyperinsulinism v2.10 SLC16A1 Sarah Leigh edited their review of gene: SLC16A1: Added comment: After consultation with Helen Brittain (Genomics England Clinical Fellow) hyperinsulinism is not part of the presenting phenotype in the biallelic cases, therefore the correct mode of inheritance for this panel is monoallelic.; Changed phenotypes to: Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.10 SLC16A1 Sarah Leigh Deleted their comment
Congenital hyperinsulinism v2.10 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: The phenotypes erythrocyte lactate transporter defect, OMIM:245340 and monocarboxylate transporter 1 deficiency, OMIM:616095 are also associated with SLC16A1 variants, however, these conditions are not relevant to this panel as they do not result in hyperinsulinism.
Congenital hyperinsulinism v2.10 SLC16A1 Sarah Leigh Phenotypes for gene: SLC16A1 were changed from Erythrocyte lactate transporter defect, OMIM:245340; Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Monocarboxylate transporter 1 deficiency, OMIM:616095 to Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021
Haematological malignancies cancer susceptibility v2.30 ERCC6L2 Angela Hamblin gene: ERCC6L2 was added
gene: ERCC6L2 was added to Haematological malignancies cancer susceptibility. Sources: Literature
Mode of inheritance for gene: ERCC6L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC6L2 were set to PMID: 30936069; PMID: 31221794
Phenotypes for gene: ERCC6L2 were set to Bone marrow failure syndrome 2, 615715; MDS; AML
Review for gene: ERCC6L2 was set to GREEN
gene: ERCC6L2 was marked as current diagnostic
Added comment: ERCC6L2 is a relatively recently discovered gene in which biallelic germline LOF variants are associated with bone marrow failure syndrome and this gene already has green status is cytopenia panels on PanelApp.

Over the last 3 years, with more widespread testing, it has become apparent that in addition to being associated with bone marrow failure it is also associated with the development of MDS / AML with the acquisition of pathogenic variants in the TP53 gene (lack of ERCC6L2 results in defects in the transcription-coupled nucleotide excision repair pathway, leading to genome instability).

Initially described in Finland, a presentation at the American Society of Haematology 2021 https://doi.org/10.1182/blood-2021-145039 illustrated that there are a number of cases in other European countries now reported. I am aware that cases have also been detected within the GMS; the cytopenia panel has demonstrated the germline mutations, whereas these were not highlighted on the WGS performed for the subsequent AML owing to the fact the gene is not currently included on the applied germline panel.

Detection of this germline variant is critical to management of these patients as currently it would mean an allogeneic HSCT is required (and as with any germline variant there would be implications for related donor choice).
Sources: Literature
Cytopenia - NOT Fanconi anaemia v1.69 CLPB Dmitrijs Rots edited their review of gene: CLPB: Added comment: additional evidence in PMID: 34115842; Changed publications to: PMID: 34140661, 34115842
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 STAT6 Boaz Palterer gene: STAT6 was added
gene: STAT6 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: STAT6 were set to Primary Atopic Disorder; Atopy; Vascular anomalies; Atopic dermamatitis; Allergy; Atopy; Hyper-IgE; elevated IgE; Eosinophilic esophagitis; Food allergies
Penetrance for gene: STAT6 were set to unknown
Mode of pathogenicity for gene: STAT6 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: STAT6 was set to RED
Added comment: Sharma et al. identified two patients from two kindreds with early-onset severe primary atopic disorder carrying de novo heterozygous STAT6 gain-of-function mutations ( https://www.medrxiv.org/content/10.1101/2022.04.25.22274265v1 ).
Extensive functional data is provided and the phenotype of GOF STAT6 variants was previously predicted (https://pubmed.ncbi.nlm.nih.gov/10747856/).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 PMS2 Dmitrijs Rots reviewed gene: PMS2: Rating: RED; Mode of pathogenicity: None; Publications: 30013564; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 C2 Dmitrijs Rots reviewed gene: C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34899688, 32113979; Phenotypes: aHUS and C3-mediated glomerulopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.864 ZFPM2 Anna de Burca gene: ZFPM2 was added
gene: ZFPM2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ZFPM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFPM2 were set to 24702427
Phenotypes for gene: ZFPM2 were set to Congenital diaphragmatic hernia
Penetrance for gene: ZFPM2 were set to Incomplete
Review for gene: ZFPM2 was set to AMBER
Added comment: Paper suggests that ZFPM2 variants may be associated with isolated congenital diaphragmatic hernia, but penetrance appears reduced. Given the apparently reduced penetrance and since isolated CDH is a relatively common congenital finding, the gene-disease association remains uncertain. Of note, variants in this gene have also been associated with 46,XY sex reversal and Tetralogy of Fallot.
Sources: Literature
Renal tubulopathies v2.54 CNNM2 Detlef Bockenhauer gene: CNNM2 was added
gene: CNNM2 was added to Renal tubulopathies. Sources: Expert list
Mode of inheritance for gene: CNNM2 was set to Other
Publications for gene: CNNM2 were set to PMID: 33600043; 30026055; 32997713; 34604137; 33859252; 24699222; 35002148; 21397062
Phenotypes for gene: CNNM2 were set to hypomagnesaemia; seizures; intellectual disability
Penetrance for gene: CNNM2 were set to Complete
Mode of pathogenicity for gene: CNNM2 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: CNNM2 was set to GREEN
Added comment: described with dominant and recessive inheritance (associated with phenotype severity), but mostly with heterozygous de novo variants
Sources: Expert list
Rhabdomyolysis and metabolic muscle disorders v1.78 TSEN54 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: TSEN54.
Dystonia, chorea or related movement disorder, childhood onset v1.235 VPS4A Sarah Leigh Tag Q2_22_rating tag was added to gene: VPS4A.
Paediatric disorders - additional genes v1.97 ADAMTS19 Sarah Leigh Tag Q2_22_expert_review tag was added to gene: ADAMTS19.
Paediatric disorders - additional genes v1.97 FOXP4 Sarah Leigh reviewed gene: FOXP4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric disorders - additional genes v1.97 FOXP4 Sarah Leigh Tag Q2_22_rating tag was added to gene: FOXP4.
Tag Q2_22_expert_review tag was added to gene: FOXP4.
Hereditary ataxia, adult onset v2.158 GLRB Sarah Leigh Tag Q2_22_rating tag was added to gene: GLRB.
Likely inborn error of metabolism v2.257 GORAB Sarah Leigh Tag Q2_22_rating tag was added to gene: GORAB.
Tag Q2_22_expert_review tag was added to gene: GORAB.
Congenital disorders of glycosylation v2.82 GORAB Sarah Leigh Tag Q2_22_rating tag was added to gene: GORAB.
Tag Q2_22_expert_review tag was added to gene: GORAB.
Mitochondrial disorders v2.107 PDK3 Sarah Leigh Tag Q2_22_rating tag was added to gene: PDK3.
Likely inborn error of metabolism v2.257 PDK3 Sarah Leigh Tag Q2_22_rating tag was added to gene: PDK3.
Congenital disorders of glycosylation v2.82 MAGT1 Sarah Leigh Tag Q2_22_rating tag was added to gene: MAGT1.
Congenital disorders of glycosylation v2.82 MAGT1 Sarah Leigh Tag Q2_22_expert_review tag was added to gene: MAGT1.
Mitochondrial disorders v2.107 PDK3 Sarah Leigh Tag Q2_22_expert_review tag was added to gene: PDK3.
Likely inborn error of metabolism v2.257 PDK3 Sarah Leigh Tag Q2_22_expert_review tag was added to gene: PDK3.
Rhabdomyolysis and metabolic muscle disorders v1.78 PHKB Sarah Leigh Tag Q2_22_expert_review tag was added to gene: PHKB.
Intellectual disability v3.1593 RYR2 Dmitrijs Rots gene: RYR2 was added
gene: RYR2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RYR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYR2 were set to 30170228
Penetrance for gene: RYR2 were set to Incomplete
Review for gene: RYR2 was set to GREEN
Added comment: In a large cohort of RYR2-related CPVT, 8% of individuals (34 of 421) were having ID of various severity. Funcional data suggest that highly damaging RYR2 variants underlie ID.
Sources: Literature
Early onset or syndromic epilepsy v2.530 RYR2 Dmitrijs Rots reviewed gene: RYR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33897349; Phenotypes: Benign Epilepsy of Childhood With Centrotemporal Spikes; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1593 ALKBH8 Konstantinos Varvagiannis edited their review of gene: ALKBH8: Changed publications to: 31079898, 33544954, 34757492
Intellectual disability v3.1593 ALKBH8 Konstantinos Varvagiannis edited their review of gene: ALKBH8: Added comment: Please consider upgrade to green rating.

2 additional relevant families reported in literature, as summarized below. While affected individuals from 3 (of the 4 total) families with the disorder were homozygous for truncating variants in the last exon (potentially corresponding to hypomorphic / incomplete LoF rather than null alleles), a more recent publication describes 2 sibs homozygous for a missense SNV with demonstrated loss-of-function in the context of normal protein levels.

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Saad et al (2020 - PMID: 33544954) report 2 sibs, born to consanguineous parents from Egypt homozygous for an ALKBH8 frameshift variant. Both exhibited global DD and ID (proband IQ of 51 / Stanford Binet test, sib: 42 using Weschler scale). There was no history of seizures. Family based exome sequencing of both sibs and parents revealed homozygosity for NM_001301010.1:c.1684delC [p.(Arg562Alafs*56))] within a region of AOH. As the authors note this variant also occurred in the last exon of the gene, likely escaping NMD and based on previous evidence from Monnies et al, hypothesize that truncating variants in the last exon represent hypomorphic alleles encoding for a partially functional protein, while protein truncating variants in earlier exons may be null alleles.

Maddirevula et al (2021 - PMID: 34757492) describe the phenotype of 2 sibs, homozygous for a missense variant. Features included severe DD and ID, microcephaly, facial dysmorphism and epilepsy (the latter limited to the elder one). Exome with autozygome analysis identified homozygosity for a missense variant (NM_138775.2:c.1874G>A / p.Arg625His) with Sanger for confirmation / segregation studies.LC-MS/MS using tRNA isolated from LCLs from the affected individual, a carrier parent and controls revealed complete loss of ALKBH8-dependent tRNA posttranscriptional modifications, the results being suggestive of abrogation of the catalytic activities of both MT and Ox domains. The protein was detected at low levels in LCLs from control and patient samples, a finding that was also supported by immunoblot analysis suggesting that the observed loss-of-function is not mediated by loss of the protein.; Changed rating: GREEN; Changed publications to: 33544954, 34757492
Intellectual disability v3.1593 CUL3 Julie Evans reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v1.97 SIX2 Julie Evans gene: SIX2 was added
gene: SIX2 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: SIX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIX2 were set to PMID: 27383657; 29315086; 26581443
Phenotypes for gene: SIX2 were set to Frontonasal dysplasia; ptosis; hearing loss
Penetrance for gene: SIX2 were set to unknown
Review for gene: SIX2 was set to GREEN
Added comment: We have a patient with a de novo deletion of the whole SIX2 gene with a compatible phenotype to the published cases (hypertelorism, ptosis, conductive hearing loss, large fontanelle).
Sources: Literature
Proteinuric renal disease v2.76 GLA John Sayer reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33928440, PMID: 33437642; Phenotypes: Proteinuria, albuminuria, end stage kidney disease, cardiomyopathy, stroke; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ataxia and cerebellar anomalies - childhood onset v2.295 ACO2 Sarah Leigh commented on gene: ACO2: PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants (the remaining 11 cases were biallelic). The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.
Ataxia and cerebellar anomalies - childhood onset v2.295 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.295 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Retinal disorders v2.274 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Mitochondrial disorders v2.107 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Intellectual disability v3.1593 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
DDG2P v2.74 ACO2 Sarah Leigh Mode of inheritance for gene: ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.864 ACO2 Sarah Leigh Mode of inheritance for gene: ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.80 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Likely inborn error of metabolism v2.257 ACO2 Sarah Leigh Tag Q2_22_NHS_review was removed from gene: ACO2.
Retinal disorders v2.274 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Mitochondrial disorders v2.107 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Intellectual disability v3.1593 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
DDG2P v2.73 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Fetal anomalies v1.863 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Possible mitochondrial disorder, nuclear genes v1.80 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Likely inborn error of metabolism v2.257 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Likely inborn error of metabolism v2.257 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Tag Q2_22_NHS_review tag was added to gene: ACO2.
Retinal disorders v2.274 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.107 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1593 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.73 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.863 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.80 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.257 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.274 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Mitochondrial disorders v2.107 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Intellectual disability v3.1593 ACO2 Sarah Leigh Publications for gene: ACO2 were set to 22405087; 25351951
DDG2P v2.73 ACO2 Sarah Leigh Publications for gene: ACO2 were set to 22405087
Fetal anomalies v1.863 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Likely inborn error of metabolism v2.257 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Possible mitochondrial disorder, nuclear genes v1.80 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Undiagnosed metabolic disorders v1.536 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Undiagnosed metabolic disorders v1.535 ACO2 Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants (the remaining 11 cases were biallelic). The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.
Undiagnosed metabolic disorders v1.535 ACO2 Sarah Leigh Mode of inheritance for gene: ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.69 ACO2 Sarah Leigh changed review comment from: PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants. The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.; to: PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants (the remaining 11 cases were biallelic). The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.
Intellectual disability v3.1592 PHF14 Sarah Leigh Tag Q2_22_rating tag was added to gene: PHF14.
Intellectual disability v3.1592 PHF14 Sarah Leigh reviewed gene: PHF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1592 PHF14 Sarah Leigh Publications for gene: PHF14 were set to 35074918
Intellectual disability v3.1591 PHF14 Sarah Leigh Classified gene: PHF14 as Amber List (moderate evidence)
Intellectual disability v3.1591 PHF14 Sarah Leigh Gene: phf14 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.273 FRMD7 Ivone Leong changed review comment from: Comment on list classification: New gene added by Mohammed Derar (University of Leeds). This gene is associated with a disease in OMIM and Gene2Phenotype.

PMID: 35157951 found patients with FRMD7 variants had grade 1 foveal hypoplasia or normal foveal morphology.

PMID: 30025138 did not perform any tests to look at foveal hypoplasia.

PMID: 33531592 showed a an FRMD7 variant in one sibling (proband) of a dizygotic twin pair. The other sibling is unaffected. The family reported nystagmus in another male sibling and the maternal grandfather; however, it is unclear whether these two individuals were also tested for FRMD7 variant. The proband had foveal hypoplasia. As it does not appear all patients with variants

PMID: 30015830 identified causative variants in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. Retinal OCT was conducted and was found to be normal.

As foveal hypoplasia does not appear to affect all individuals with FRMD7 variants, this gene has been referred to NHS GMS working group to determine if this gene is appropriate for this panel.; to: Comment on list classification: New gene added by Mohammed Derar (University of Leeds). This gene is associated with a disease in OMIM and Gene2Phenotype.

PMID: 35157951 found patients with FRMD7 variants had grade 1 foveal hypoplasia or normal foveal morphology.

PMID: 30025138 did not perform any tests to look at foveal hypoplasia.

PMID: 33531592 showed a an FRMD7 variant in one sibling (proband) of a dizygotic twin pair. The other sibling is unaffected. The family reported nystagmus in another male sibling and the maternal grandfather; however, it is unclear whether these two individuals were also tested for FRMD7 variant. The proband had foveal hypoplasia. As it does not appear all patients with variants

PMID: 30015830 identified causative variants in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. Retinal OCT was conducted and was found to be normal.

Nystagmus is the presenting feature and foveal hypoplasia does not appear to affect all individuals with FRMD7 variants. This gene is already Green on the "Albinism or congenital nystagmus" (version 1.23) panel; therefore, this gene will remain as Amber for now.
Retinal disorders v2.273 FRMD7 Ivone Leong Tag Q2_22_rating was removed from gene: FRMD7.
Tag Q2_22_expert_review was removed from gene: FRMD7.
Tag Q2_22_NHS_review was removed from gene: FRMD7.
Retinal disorders v2.273 AHR Eleanor Williams Publications for gene: AHR were set to 29726989; 31896775
Retinal disorders v2.272 AHR Eleanor Williams commented on gene: AHR
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams Tag watchlist was removed from gene: KCNJ16.
Tag Q2_22_rating tag was added to gene: KCNJ16.
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams changed review comment from: Comment on list classification: Rating this gene as amber, 7 cases reported in PMID:33811157 but details of the nature of the hearing loss could not be obtained due to inaccessibility of the publication.; to: Comment on list classification: Rating this gene as amber, but with a recommendation of green rating following GMS review. 7 families reported in PMID:33811157 with hearing loss developing in affected individuals in childhood or adolescence.
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams changed review comment from: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR)

PMID:33811157 - Schlingmann et al 2021 - unable to access publication. Abstract does not give numbers of cases but OMIM states that "In 8 patients, including 1 sib pair, with hypokalemic tubulopathy and deafness, Schlingmann et al. (2021) identified homozygous or compound heterozygous mutations in the KCNJ16 gene". Details of the hearing loss could not be acertained.

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned.
Sources: Literature; to: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR)

PMID:33811157 - Schlingmann et al 2021 - report 8 patients from 7 families with hypokalemic tubulopathy and deafness. All patients had acidosis and sensorineural deafness. Hearing loss was diagnosed in childhood or adolescence. All were found to have homozygous or compound heterozygous variants in the KCNJ16 gene. 6 different variants were identified, either missense or nonsesnse. Functional studies showed that variants affect the function of heteromeric potassium channels.

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned.
Sources: Literature
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams changed review comment from: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR)

PMID:33811157 - Schlingmann et al 2021 - unable to access publication. Abstract does not give numbers of cases but OMIM states that "In 8 patients, including 1 sib pair, with hypokalemic tubulopathy and deafness, Schlingmann et al. (2021) identified homozygous or compound heterozygous mutations in the KCNJ16 gene"

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype.; to: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR)

PMID:33811157 - Schlingmann et al 2021 - report 8 patients from 7 families with hypokalemic tubulopathy and deafness. All patients had acidosis and sensorineural deafness. All were found to have homozygous or compound heterozygous variants in the KCNJ16 gene. 6 different variants were identified, either missense or nonsesnse.

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 c.142A>T; p.(Lys48*) in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. No loss of hearing was noted.
Intellectual disability v3.1590 MED13 Catherine Snow Tag Q2_22_rating tag was added to gene: MED13.
Tag Q2_22_NHS_review tag was added to gene: MED13.
Intellectual disability v3.1590 MED13 Catherine Snow reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33931951; Phenotypes: Intellectual developmental disorder, autosomal dominant 61 OMIM:618009; Mode of inheritance: None
Renal tubulopathies v2.54 SEC61A1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: SEC61A1.
Tag Q2_21_expert_review was removed from gene: SEC61A1.
Tag Q2_22_phenotype tag was added to gene: SEC61A1.
Tag Q2_22_expert_review tag was added to gene: SEC61A1.
Renal tubulopathies v2.54 SEC61A1 Eleanor Williams Tag Q2_21_phenotype tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 HCK Boaz Palterer gene: HCK was added
gene: HCK was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: HCK was set to Unknown
Publications for gene: HCK were set to 34536415
Phenotypes for gene: HCK were set to Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease
Penetrance for gene: HCK were set to unknown
Mode of pathogenicity for gene: HCK 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: HCK was set to RED
Added comment: Kanderova et al. described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis.
A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified.
Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines.
Sources: Literature
Retinal disorders v2.272 SLC38A8 Eleanor Williams commented on gene: SLC38A8: Green review from Mohammed Derar on green gene so no change in rating needed. Phenotypes updated.
Retinal disorders v2.272 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216 to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; chiasmal misrouting
DDG2P v2.72 FGF5 Eleanor Williams commented on gene: FGF5
DDG2P v2.72 PLCB4 Eleanor Williams commented on gene: PLCB4
Fetal anomalies v1.862 PLCB4 Eleanor Williams Classified gene: PLCB4 as Amber List (moderate evidence)
Fetal anomalies v1.862 PLCB4 Eleanor Williams Added comment: Comment on list classification: Leaving the rating of this gene as amber just now, but there are sufficient cases to promote to green following GMS review.
Fetal anomalies v1.862 PLCB4 Eleanor Williams Gene: plcb4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.861 PLCB4 Eleanor Williams Mode of inheritance for gene: PLCB4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.860 PLCB4 Eleanor Williams Tag Q2_22_rating tag was added to gene: PLCB4.
Fetal anomalies v1.860 PLCB4 Eleanor Williams reviewed gene: PLCB4: Rating: ; Mode of pathogenicity: None; Publications: 22560091, 23315542, 28328130, 23913798; Phenotypes: Auriculocondylar syndrome 2, OMIM:614669, auriculocondylar syndrome 2, MONDO:0013845; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting v2.68 PLCB4 Eleanor Williams Tag Q2_22_rating tag was added to gene: PLCB4.
Clefting v2.68 PLCB4 Eleanor Williams edited their review of gene: PLCB4: Added comment: PMID: 28328130 - Romanelli-Tavares et al 2017 - report 2 patients (1 sporadic, 1 familial) with previous published phenotypic descriptions of Auriculocondylar syndrome in which heterozygous missense variants were found in PLCB4 after sequencing PLCB4, GNAI3,and EDN1. Cleft palate was noted in 2/7 members of the familial case.

This is a 3rd case in which cleft palate is reported in association with PLCB4 variants and therefore there is sufficient evidence to promote this gene to green following GMS review.; Changed rating: GREEN; Changed publications to: 28328130
Clefting v2.68 PLCB4 Eleanor Williams Publications for gene: PLCB4 were set to 16114046; 32201334; 27007857; 23913798; 2560091; 23315542
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 UBA1 Eleanor Williams Classified gene: UBA1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 UBA1 Eleanor Williams Added comment: Comment on list classification: The rating of this gene has been left as red for now, as it is a somatic variant. Advice will be sought as to the best rating. It is also being reviewed on the 'Autoinflammatory disorders' wet lab panel by the Test Evaluation Working Group.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 UBA1 Eleanor Williams Gene: uba1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.549 UBA1 Eleanor Williams Tag Q2_22_expert_review tag was added to gene: UBA1.
Tag Q2_22_NHS_review tag was added to gene: UBA1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.549 UBA1 Eleanor Williams Tag to_be_confirmed_NHSE was removed from gene: UBA1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.549 UBA1 Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: UBA1.
Tag Q2_22_rating tag was added to gene: UBA1.
Retinal disorders v2.271 PAX6 Catherine Snow reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric disorders - additional genes v1.97 FOXL2 Eleanor Williams Tag Q2_22_phenotype was removed from gene: FOXL2.
Tag Q2_22_expert_review was removed from gene: FOXL2.
Tag Q2_22_NHS_review was removed from gene: FOXL2.
Paediatric disorders - additional genes v1.97 FOXL2 Eleanor Williams Classified gene: FOXL2 as Red List (low evidence)
Paediatric disorders - additional genes v1.97 FOXL2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red for just now. Sufficient evidence for a gene-disease association if the phenotype is appropriate for the panel. Waiting for feedback from the clinical team.
Paediatric disorders - additional genes v1.97 FOXL2 Eleanor Williams Gene: foxl2 has been classified as Red List (Low Evidence).
Retinal disorders v2.271 FRMD7 Ivone Leong Phenotypes for gene: FRMD7 were changed from Infantile nystagmus; foveal hypoplasia to Nystagmus 1, congenital, X-linked, OMIM:310700; Nystagmus, infantile periodic alternating, X-linked, OMIM:310700; foveal hypoplasia, MONDO:0044203
Retinal disorders v2.270 FRMD7 Ivone Leong Publications for gene: FRMD7 were set to 30025138; 24688117
Retinal disorders v2.269 FRMD7 Ivone Leong Classified gene: FRMD7 as Amber List (moderate evidence)
Retinal disorders v2.269 FRMD7 Ivone Leong Added comment: Comment on list classification: New gene added by Mohammed Derar (University of Leeds). This gene is associated with a disease in OMIM and Gene2Phenotype.

PMID: 35157951 found patients with FRMD7 variants had grade 1 foveal hypoplasia or normal foveal morphology.

PMID: 30025138 did not perform any tests to look at foveal hypoplasia.

PMID: 33531592 showed a an FRMD7 variant in one sibling (proband) of a dizygotic twin pair. The other sibling is unaffected. The family reported nystagmus in another male sibling and the maternal grandfather; however, it is unclear whether these two individuals were also tested for FRMD7 variant. The proband had foveal hypoplasia. As it does not appear all patients with variants

PMID: 30015830 identified causative variants in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. Retinal OCT was conducted and was found to be normal.

As foveal hypoplasia does not appear to affect all individuals with FRMD7 variants, this gene has been referred to NHS GMS working group to determine if this gene is appropriate for this panel.
Retinal disorders v2.269 FRMD7 Ivone Leong Gene: frmd7 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.268 FRMD7 Ivone Leong Tag Q2_22_rating tag was added to gene: FRMD7.
Retinal disorders v2.268 FRMD7 Ivone Leong Tag Q2_22_expert_review tag was added to gene: FRMD7.
Tag Q2_22_NHS_review tag was added to gene: FRMD7.
Retinal disorders v2.268 FRMD7 Ivone Leong Publications for gene: FRMD7 were set to Choi et al. (2018) (PMID: 30025138); Thomas et al. (2014) (PMID:24688117)
Paediatric or syndromic cardiomyopathy v1.73 LMOD2 Ivone Leong Phenotypes for gene: LMOD2 were changed from dilated cardiomyopathy to dilated cardiomyopathy, MONDO:0005021
Paediatric or syndromic cardiomyopathy v1.72 LMOD2 Ivone Leong Tag Q2_22_NHS_review tag was added to gene: LMOD2.
Paediatric or syndromic cardiomyopathy v1.72 LMOD2 Ivone Leong Tag Q2_22_rating tag was added to gene: LMOD2.
Paediatric or syndromic cardiomyopathy v1.72 LMOD2 Ivone Leong Classified gene: LMOD2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.72 LMOD2 Ivone Leong Added comment: Comment on list classification: New gene added by Julia Baptista (Faculty of Health, University of Plymouth). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Based on the expert review this gene should be rated Green at the next review as there is enough evidence to support a gene-disease association.
Paediatric or syndromic cardiomyopathy v1.72 LMOD2 Ivone Leong Gene: lmod2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.71 LMOD2 Ivone Leong Publications for gene: LMOD2 were set to PMID: 35082396; 35188328; 34888509; 31517052
Optic neuropathy v2.69 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.69 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Tag Q2_22_NHS_review tag was added to gene: ACO2.
Optic neuropathy v2.69 ACO2 Sarah Leigh Publications for gene: ACO2 were set to 25351951; 22405087
Cholestasis v1.110 ZFYVE19 Sarah Leigh Publications for gene: ZFYVE19 were set to 32737136
Cholestasis v1.109 ZFYVE19 Sarah Leigh Phenotypes for gene: ZFYVE19 were changed from Cholestasis to Cholestasis, progressive familial intrahepatic, 9, OMIM:619849
Cholestasis v1.108 YARS Sarah Leigh Publications for gene: YARS were set to 30304524; 29232904; 27633801
Retinal disorders v2.267 RNU4ATAC Sarah Leigh edited their review of gene: RNU4ATAC: Added comment: Associated with relevant phenotypes in OMIM and as definitive Gen2Phen gene for Microcephalic osteodysplastic primordial dwarfism, type I (OMIM:210710) which sometimes includes features of Lowry-Wood syndrome (OMIM:226960) and Roifman syndrome (OMIM:616651) making it relevant to this ophthalimic panel. At least six variants have been reported in at least three cases of Lowry-Wood syndrome (OMIM:226960) and at least six variants have been reported in at least three cases of Roifman syndrome (OMIM:616651).
Hannah Knight (Moorfields Eye Hospital) has also reported two further variants in a case of Lowry-Wood syndrome (OMIM:226960) where the patient shows retinal dystrophy.; Changed rating: GREEN
Retinal disorders v2.267 RNU4ATAC Sarah Leigh Tag Q2_22_rating tag was added to gene: RNU4ATAC.
Tag Q2_22_NHS_review tag was added to gene: RNU4ATAC.
Retinal disorders v2.267 RNU4ATAC Sarah Leigh Classified gene: RNU4ATAC as Amber List (moderate evidence)
Retinal disorders v2.267 RNU4ATAC Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Retinal disorders v2.267 RNU4ATAC Sarah Leigh Gene: rnu4atac has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.266 RNU4ATAC Sarah Leigh Publications for gene: RNU4ATAC were set to PMID: 2801768; 29265708; 30368667
Retinal disorders v2.265 RNU4ATAC Sarah Leigh Phenotypes for gene: RNU4ATAC were changed from Retinal dystrophy; recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia; extreme intrauterine growth retardation; facial dysmorphism; microcephaly; short stature to Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Roifman syndrome, OMIM:616651
Retinal disorders v2.264 CTNNA1 Sarah Leigh Publications for gene: CTNNA1 were set to 26691986; 33497368
Retinal disorders v2.263 ARSG Sarah Leigh edited their review of gene: ARSG: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least six variants have been reported in at least five unrelated cases of Usher syndrome, type IV (OMIM:618144).; Changed rating: GREEN
Retinal disorders v2.263 ARSG Sarah Leigh Classified gene: ARSG as Amber List (moderate evidence)
Retinal disorders v2.263 ARSG Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Retinal disorders v2.263 ARSG Sarah Leigh Gene: arsg has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.262 ARSG Sarah Leigh Tag Q2_22_rating tag was added to gene: ARSG.
Tag Q2_22_NHS_review tag was added to gene: ARSG.
Retinal disorders v2.262 ARSG Sarah Leigh Publications for gene: ARSG were set to
Retinal disorders v2.261 ARSG Sarah Leigh Phenotypes for gene: ARSG were changed from to Usher syndrome, type IV, OMIM:618144
Retinal disorders v2.260 ARSG Sarah Leigh Mode of inheritance for gene: ARSG was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1590 SRRM2 Sarah Leigh edited their review of gene: SRRM2: Added comment: Not associated with a phenotype in OMIM and as definitive Gen2Phen gene for SRRM2-related developmental disorder (monoallelic). At least 22 loss of function SRRM2 variants have been reported in PMID: 35567594 in unrelated cases of which 16/20 exhibit variable mild intellectual disability.; Changed rating: GREEN
Intellectual disability v3.1590 SRRM2 Sarah Leigh Tag Q2_22_rating tag was added to gene: SRRM2.
Intellectual disability v3.1590 SRRM2 Sarah Leigh Classified gene: SRRM2 as Amber List (moderate evidence)
Intellectual disability v3.1590 SRRM2 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 v3.1590 SRRM2 Sarah Leigh Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1589 SRRM2 Sarah Leigh changed review comment from: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to be associated with SRRM2 variants.; to: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to have a definitive association with SRRM2 variants.
Intellectual disability v3.1589 SRRM2 Sarah Leigh Added comment: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to be associated with SRRM2 variants.
Intellectual disability v3.1589 SRRM2 Sarah Leigh Phenotypes for gene: SRRM2 were changed from Developmental disorders to SRRM2-related developmental disorder (monoallelic)
Intellectual disability v3.1588 SRRM2 Sarah Leigh Publications for gene: SRRM2 were set to 33057194
Early onset or syndromic epilepsy v2.530 PRPF8 Sarah Leigh Entity copied from Intellectual disability v3.1587
Early onset or syndromic epilepsy v2.530 PRPF8 Sarah Leigh gene: PRPF8 was added
gene: PRPF8 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q2_22_rating tags were added to gene: PRPF8.
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 20811066; 23714367; 30420816; 31696658; 35543142
Phenotypes for gene: PRPF8 were set to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059
Penetrance for gene: PRPF8 were set to unknown
Intellectual disability v3.1587 PRPF8 Sarah Leigh edited their review of gene: PRPF8: Added comment: Associated with Retinitis pigmentosa 13 (OMIM:600059) in OMIM, but not with PRPF8-related developmental disorder (monoallelic) and as a both RD and IF Gen2Phen gene for PRPF8-related developmental disorder (monoallelic). PMID: 35543142 reports 14 PRPF8 variants in unrelated cases (12/14 variants were confirmed as de novo). Intellectual disability was observed in 13/14 of these cases and seizures were evident in 4/14 cases.; Changed rating: GREEN
Intellectual disability v3.1587 PRPF8 Sarah Leigh Added comment: Comment on phenotypes: Gen2Phen phenotype: PRPF8-related developmental disorder (monoallelic) in addition to Retinitis pigmentosa 13
Intellectual disability v3.1587 PRPF8 Sarah Leigh Phenotypes for gene: PRPF8 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, OMIM:600059 to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059
Intellectual disability v3.1586 PRPF8 Sarah Leigh Classified gene: PRPF8 as Amber List (moderate evidence)
Intellectual disability v3.1586 PRPF8 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 v3.1586 PRPF8 Sarah Leigh Gene: prpf8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1585 PRPF8 Sarah Leigh Tag Q2_22_rating tag was added to gene: PRPF8.
Intellectual disability v3.1585 PRPF8 Sarah Leigh Phenotypes for gene: PRPF8 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059 to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, OMIM:600059
Intellectual disability v3.1584 PRPF8 Sarah Leigh Publications for gene: PRPF8 were set to 35543142
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams changed review comment from: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases to promote to green. This gene has been proposed for inclusion on this panel through the NHS Test directory application group and therefore is not tagged for GMS review but will be promoted in the next cycle of updates.; to: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases to promote to green. This gene has been proposed for inclusion on this panel through the NHS Test directory application route and therefore is not tagged for GMS review but will be promoted in the next cycle of updates.
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams Classified gene: CACNA1C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases to promote to green. This gene has been proposed for inclusion on this panel through the NHS Test directory application group and therefore is not tagged for GMS review but will be promoted in the next cycle of updates.
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.528 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from to Timothy syndrome OMIM:601005
Early onset or syndromic epilepsy v2.527 CACNA1C Eleanor Williams Publications for gene: CACNA1C were set to
Early onset or syndromic epilepsy v2.526 CACNA1C Eleanor Williams reviewed gene: CACNA1C: Rating: ; Mode of pathogenicity: None; Publications: 15454078, 15863612, 28371864; Phenotypes: Timothy syndrome OMIM:601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric disorders - additional genes v1.96 FOXL2 Catherine Snow Tag Q2_22_phenotype tag was added to gene: FOXL2.
Tag Q2_22_expert_review tag was added to gene: FOXL2.
Tag Q2_22_NHS_review tag was added to gene: FOXL2.
Intellectual disability v3.1583 DROSHA Sarah Leigh reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1583 DROSHA Sarah Leigh Classified gene: DROSHA as Amber List (moderate evidence)
Intellectual disability v3.1583 DROSHA Sarah Leigh Gene: drosha has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1582 DROSHA Sarah Leigh Tag locus-type-rna-micro tag was added to gene: DROSHA.
Tag Q2_22_rating tag was added to gene: DROSHA.
Skeletal dysplasia v2.207 DROSHA Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.526
Skeletal dysplasia v2.207 DROSHA Sarah Leigh gene: DROSHA was added
gene: DROSHA was added to Skeletal dysplasia. Sources: Expert Review Amber,Literature
locus-type-rna-micro, Q2_22_rating tags were added to gene: DROSHA.
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Severe microcephaly v2.301 DROSHA Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.526
Severe microcephaly v2.301 DROSHA Sarah Leigh gene: DROSHA was added
gene: DROSHA was added to Severe microcephaly. Sources: Expert Review Amber,Literature
locus-type-rna-micro, Q2_22_rating tags were added to gene: DROSHA.
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Tag Q2_22_rating tag was added to gene: DROSHA.
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Tag locus-type-rna-micro tag was added to gene: DROSHA.
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Classified gene: DROSHA as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Gene: drosha has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.525 CACNA1C Eleanor Williams gene: CACNA1C was added
gene: CACNA1C was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: CACNA1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1582 SNORD118 Sarah Leigh edited their review of gene: SNORD118: Added comment: In response to Ian Berry's (Leeds Genetics Laboratory) review, SNORD118 should be promoted to green on this panel.; Changed rating: GREEN
Intellectual disability v3.1582 SNORD118 Sarah Leigh Tag Q2_22_rating tag was added to gene: SNORD118.
Tag Q2_22_NHS_review tag was added to gene: SNORD118.
Intellectual disability v3.1582 SNORD118 Sarah Leigh Classified gene: SNORD118 as Amber List (moderate evidence)
Intellectual disability v3.1582 SNORD118 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 v3.1582 SNORD118 Sarah Leigh Gene: snord118 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1581 SCAF4 Sarah Leigh edited their review of gene: SCAF4: Added comment: In repsonse to Ian Berry's (Leeds Genetics Laboratory) review, which also reports an additional patient with a de novo truncating variant, there is sufficient evidence for SCAF4 to be green on this panel.; Changed rating: GREEN
Intellectual disability v3.1581 SCAF4 Sarah Leigh Tag watchlist was removed from gene: SCAF4.
Tag Q2_22_rating tag was added to gene: SCAF4.
Tag Q2_22_NHS_review tag was added to gene: SCAF4.
Intellectual disability v3.1581 SCAF4 Sarah Leigh Classified gene: SCAF4 as Amber List (moderate evidence)
Intellectual disability v3.1581 SCAF4 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 v3.1581 SCAF4 Sarah Leigh Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.107 GALK1 Ivone Leong Tag Q2_22_rating tag was added to gene: GALK1.
Tag Q2_22_expert_review tag was added to gene: GALK1.
Cholestasis v1.107 GBE1 Ivone Leong Tag Q2_22_rating tag was added to gene: GBE1.
Tag Q2_22_expert_review tag was added to gene: GBE1.
Hypertrophic cardiomyopathy v2.39 ALPK3 Ivone Leong Tag Q2_22_rating tag was added to gene: ALPK3.
Hypertrophic cardiomyopathy v2.39 ALPK3 Ivone Leong Added comment: Comment on publications: New publications added.
Hypertrophic cardiomyopathy v2.39 ALPK3 Ivone Leong Publications for gene: ALPK3 were set to 26846950; 27106955; 32480058; 28630369; 30046096; 31074094; 21441111
Paediatric disorders - additional genes v1.96 FOXL2 Catherine Snow changed review comment from: Suitable number of cases with pathogenic variants associated with condition. Gene associated with 2 forms of blepharophimosis/ptosis/epicanthus inversus syndrome. Type 1, eyelid abnormalities are associated with ovarian failure. Type 2 has eyelid abnormalities. As other genes associated with blepharophimosis are not on this panel querying clinical tam to see if gene phenotype if suitable for panel; to: Suitable number of cases with pathogenic variants associated with condition. Gene associated with 2 forms of blepharophimosis/ptosis/epicanthus inversus syndrome. Type 1, eyelid abnormalities are associated with ovarian failure. Type 2 has eyelid abnormalities. As other genes associated with blepharophimosis are not on this panel querying clinical team to see if gene phenotype if suitable for panel.
Paediatric disorders - additional genes v1.96 FOXL2 Catherine Snow reviewed gene: FOXL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Blepharophimosis, epicanthus inversus, and ptosis, type 1 OMIM:110100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1580 SNORD118 Ian Berry reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism v2.256 IDH1 Sarah Leigh Publications for gene: IDH1 were set to PMID: 33340416
Mitochondrial disorders v2.106 IDH1 Sarah Leigh Publications for gene: IDH1 were set to PMID: 33340416
Malformations of cortical development v2.144 EMX2 Sarah Leigh Publications for gene: EMX2 were set to 8528262; 9359037; 18409201
Malformations of cortical development v2.143 EMX2 Sarah Leigh reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: 18409201, 17506092; Mode of inheritance: None
Malformations of cortical development v2.143 EMX2 Sarah Leigh Tag Q2_22_rating tag was added to gene: EMX2.
Tag Q2_22_expert_review tag was added to gene: EMX2.
Mitochondrial disorders v2.105 MARS2 Sarah Leigh changed review comment from: In response to Zornitza Stark's (Australian Genomics), review 20 Mar 2020: which questions if there is sufficient evidence for both Combined oxidative phosphorylation deficiency 25 (OMIM:616430) and Spastic ataxia 3, autosomal recessive (OMIM:611390) to be green on this panel based on copy number variants in three families with Spastic ataxia 3, autosomal recessive (OMIM:611390) and Combined oxidative phosphorylation deficiency 25 (OMIM:616430) in one family who was compound heterozygous for a missense and a terminating variant. No other variants appear to have bee reported in the literature to date.; to: In response to Zornitza Stark's (Australian Genomics), review 20 Mar 2020: which questions if there is sufficient evidence for both Combined oxidative phosphorylation deficiency 25 (OMIM:616430) and Spastic ataxia 3, autosomal recessive (OMIM:611390) to be green on this panel, based on copy number variants in three families with Spastic ataxia 3, autosomal recessive (OMIM:611390)(PMID: 22448145) and Combined oxidative phosphorylation deficiency 25 (OMIM:616430)(PMID: 25754315) in one family who was compound heterozygous for a missense and a terminating variant. No other variants appear to have been reported in the literature to date.
Mitochondrial disorders v2.105 MARS2 Sarah Leigh reviewed gene: MARS2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.303 MARS2 Sarah Leigh Phenotypes for gene: MARS2 were changed from Spastic ataxia 3, autosomal recessive to Spastic ataxia 3, autosomal recessive, OMIM:611390
Mitochondrial disorders v2.105 COX14 Sarah Leigh changed review comment from: In response to Zornitza Stark's review, that only a single COX14 variant has been published in cases of Fatal Neonatal Lactic Acidosis (PMID:22243966), it would be beneficial to recieve confirmation from the NHS that COX14 is still used in standard diagnostic practice.; to: In response to Zornitza Stark's (Australian Genomics), review 18 Mar 2020: that only a single COX14 variant has been published in cases of Fatal Neonatal Lactic Acidosis (PMID:22243966), it would be beneficial to recieve confirmation from the NHS that COX14 is still used in standard diagnostic practice.
Mitochondrial disorders v2.105 MARS2 Sarah Leigh Tag missense was removed from gene: MARS2.
Tag Q2_22_rating tag was added to gene: MARS2.
Tag Q2_22_expert_review tag was added to gene: MARS2.
Mitochondrial disorders v2.105 MARS2 Sarah Leigh Publications for gene: MARS2 were set to PMID: 22448145; 25754315
Mitochondrial disorders v2.104 COX14 Sarah Leigh Tag Q2_21_rating was removed from gene: COX14.
Tag Q2_22_rating tag was added to gene: COX14.
Mitochondrial disorders v2.104 COX14 Sarah Leigh reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v2.104 COX14 Sarah Leigh Tag Q2_21_rating tag was added to gene: COX14.
Tag Q2_22_expert_review tag was added to gene: COX14.
Mitochondrial disorders v2.104 COX14 Sarah Leigh Publications for gene: COX14 were set to PMID: 22243966
Dystonia, chorea or related movement disorder, childhood onset v1.235 SNORD118 Sarah Leigh edited their review of gene: SNORD118: Added comment: Associated with relevant phenotype in OMIM and as both RD and IF Gen2Phen gene. Numervous variants have been reported in cases with Leukoencephalopathy, brain calcifications, and cysts (OMIM:614561), which include features of motor involvement (PMID: 33029936).; Changed rating: GREEN
Dystonia, chorea or related movement disorder, childhood onset v1.235 SNORD118 Sarah Leigh Publications for gene: SNORD118 were set to 27571260
Dystonia, chorea or related movement disorder, childhood onset v1.234 SNORD118 Sarah Leigh Tag locus-type-small-nucleolar tag was added to gene: SNORD118.
Tag Q2_22_rating tag was added to gene: SNORD118.
Dystonia, chorea or related movement disorder, childhood onset v1.234 SNORD118 Sarah Leigh Phenotypes for gene: SNORD118 were changed from Leukoencephalopathy, brain calcifications, and cysts MIM#614561 to Leukoencephalopathy, brain calcifications, and cyst, OMIM:614561
Dystonia, chorea or related movement disorder, childhood onset v1.233 SNORD118 Sarah Leigh Classified gene: SNORD118 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.233 SNORD118 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.233 SNORD118 Sarah Leigh Gene: snord118 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.238 SNORD118 Sarah Leigh Classified gene: SNORD118 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.238 SNORD118 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - childhood onset v1.238 SNORD118 Sarah Leigh Gene: snord118 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.237 SNORD118 Sarah Leigh Tag Q2_22_rating tag was added to gene: SNORD118.
White matter disorders and cerebral calcification - childhood onset v1.237 SNORD118 Sarah Leigh Tag locus-type-small-nucleolar tag was added to gene: SNORD118.
White matter disorders and cerebral calcification - childhood onset v1.237 SNORD118 Sarah Leigh Publications for gene: SNORD118 were set to 28177126; 27571260
White matter disorders and cerebral calcification - childhood onset v1.236 SNORD118 Sarah Leigh Tag Q2_22_NHS_review tag was added to gene: SNORD118.
Intellectual disability v3.1580 SRRM2 Konstantinos Varvagiannis changed review comment from: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2 reported. DD was a universal feature, with ID present in some (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].; to: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2. DD was a universal feature, with ID present in some affected individuals (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].
Intellectual disability v3.1580 SRRM2 Konstantinos Varvagiannis reviewed gene: SRRM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35567594, 33057194; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of the head or neck, Small hand, Short foot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hypertrophic cardiomyopathy v2.38 ALPK3 Luis Lopes reviewed gene: ALPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34263907, 35583889; Phenotypes: Hypertrophic Cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.524 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA 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: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one).

Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ]

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Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants.

Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features.

Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq.

DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse.

As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided):
- in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity
- in Drosophila playing a role in the development of ovary, eye, nervous system etc.
- in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects.

Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes.

miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s.

Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs).

Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided).

Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly.

Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele.

The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction.

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Intellectual disability v3.1580 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA 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: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one).

Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ]

-----

Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants.

Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features.

Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq.

DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse.

As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided):
- in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity
- in Drosophila playing a role in the development of ovary, eye, nervous system etc.
- in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects.

Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes.

miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s.

Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs).

Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided).

Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly.

Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele.

The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction.

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Unexplained young onset end-stage renal disease v1.37 EMP2 Eleanor Williams Classified gene: EMP2 as Green List (high evidence)
Unexplained young onset end-stage renal disease v1.37 EMP2 Eleanor Williams Added comment: Comment on list classification: The rating of this gene has been left as green, but with a recommendation for demotion to amber following expert review of the evidence.
Unexplained young onset end-stage renal disease v1.37 EMP2 Eleanor Williams Gene: emp2 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v1.36 EMP2 Eleanor Williams commented on gene: EMP2: In a review of this gene on the Proteinuric renal disease panel, Daniel Gale (UCL) states "A single study from 2014 (PMID: 24814193) reports biallelic (1 x nonsense and 2 x missense) rare EMP2 variants in 4 individuals with steroid sensitive nephrotic syndrome from 3 (out of 1600) nephrotic syndrome cases studied and this finding has not been replicated in further studies of SSNS (PMID: 29058154) or knockout mice (PMID: 31508419). Subsequent data from GnomAD does not show evidence of depletion of LoF or missense variation in this gene and no signal has been reported in gene-based burden or variant testing of large cohorts. Therefore further evidence is needed for biallelic mutations in this gene to be clinically reportable."
Unexplained young onset end-stage renal disease v1.36 EMP2 Eleanor Williams Tag Q2_22_rating tag was added to gene: EMP2.
Unexplained young onset end-stage renal disease v1.36 EMP2 Eleanor Williams Tag Q2_21_rating was removed from gene: EMP2.
Unexplained young onset end-stage renal disease v1.36 EMP2 Eleanor Williams Tag Q2_21_rating tag was added to gene: EMP2.
Proteinuric renal disease v2.76 EMP2 Eleanor Williams Classified gene: EMP2 as Green List (high evidence)
Proteinuric renal disease v2.76 EMP2 Eleanor Williams Added comment: Comment on list classification: The rating of this gene has been left as green, but with a recommendation for demotion to amber following expert review of the evidence.
Proteinuric renal disease v2.76 EMP2 Eleanor Williams Gene: emp2 has been classified as Green List (High Evidence).
Proteinuric renal disease v2.75 EMP2 Eleanor Williams Tag Q2_22_rating tag was added to gene: EMP2.
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams changed review comment from: Comment on list classification: Rating this gene as amber, 7 cases reported in PMID:33811157 but details of how many had hearing loss or the details of the nature of the hearing loss could not be obtained due to inaccessibility of the publication.; to: Comment on list classification: Rating this gene as amber, 7 cases reported in PMID:33811157 but details of the nature of the hearing loss could not be obtained due to inaccessibility of the publication.
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams Classified gene: KCNJ16 as Amber List (moderate evidence)
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams Added comment: Comment on list classification: Rating this gene as amber, 7 cases reported in PMID:33811157 but details of how many had hearing loss or the details of the nature of the hearing loss could not be obtained due to inaccessibility of the publication.
Monogenic hearing loss v2.246 KCNJ16 Eleanor Williams Gene: kcnj16 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.245 KCNJ16 Eleanor Williams gene: KCNJ16 was added
gene: KCNJ16 was added to Hearing loss. Sources: Literature
watchlist tags were added to gene: KCNJ16.
Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNJ16 were set to 33811157; 33840812
Phenotypes for gene: KCNJ16 were set to Hypokalemic tubulopathy and deafness, OMIM:619406
Review for gene: KCNJ16 was set to AMBER
Added comment: Associated with Hypokalemic tubulopathy and deafness OMIM#619406 (AR)

PMID:33811157 - Schlingmann et al 2021 - unable to access publication. Abstract does not give numbers of cases but OMIM states that "In 8 patients, including 1 sib pair, with hypokalemic tubulopathy and deafness, Schlingmann et al. (2021) identified homozygous or compound heterozygous mutations in the KCNJ16 gene". Details of the hearing loss could not be acertained.

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned.
Sources: Literature
Renal tubulopathies v2.54 SEC61A1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel. There are sufficient cases with Autosomal dominant tubulointerstitial kidney to rate green.; to: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the associated disease phenotype fulfils the eligibility criteria for this panel. There are sufficient cases with Autosomal dominant tubulointerstitial kidney to rate green.
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams Classified gene: KCNJ16 as Amber List (moderate evidence)
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber with a recommendation of green rating following GMS review.
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams Gene: kcnj16 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.53 KCNJ16 Eleanor Williams Tag Q2_22_rating tag was added to gene: KCNJ16.
Renal tubulopathies v2.53 KCNJ16 Eleanor Williams Phenotypes for gene: KCNJ16 were changed from Renal tubulopathy; deafness to Hypokalemic tubulopathy and deafness, OMIM:619406
Renal tubulopathies v2.52 KCNJ16 Eleanor Williams commented on gene: KCNJ16
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel; to: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel. There are sufficient cases with Autosomal dominant tubulointerstitial kidney to rate green.
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams Classified gene: SEC61A1 as Amber List (moderate evidence)
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.51 SEC61A1 Eleanor Williams Publications for gene: SEC61A1 were set to PMID: 33185949; 27392076; 31488840
Renal tubulopathies v2.50 SEC61A1 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: SEC61A1.
Tag Q2_22_rating tag was added to gene: SEC61A1.
Renal tubulopathies v2.50 SEC61A1 Eleanor Williams reviewed gene: SEC61A1: Rating: ; Mode of pathogenicity: None; Publications: 33185949, 30586318, 27392076, 31488840; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.45 IFT140 Eleanor Williams Tag Q2_22_NHS_review tag was added to gene: IFT140.
Cystic kidney disease v2.45 IFT140 Eleanor Williams Tag Q2_22_rating tag was added to gene: IFT140.
Cystic kidney disease v2.45 IFT140 Eleanor Williams Classified gene: IFT140 as Amber List (moderate evidence)
Cystic kidney disease v2.45 IFT140 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber with a recommendation for GREEN rating following GMS review.
Cystic kidney disease v2.45 IFT140 Eleanor Williams Gene: ift140 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.44 IFT140 Eleanor Williams Phenotypes for gene: IFT140 were changed from Cystic kidney disease; chronic kidney disease to Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964; cystic kidney disease, MONDO:0002473
Cystic kidney disease v2.43 IFT140 Eleanor Williams Publications for gene: IFT140 were set to 34890546
Cystic kidney disease v2.42 IFT140 Eleanor Williams Added comment: Comment on mode of inheritance: As reviewer notes there are several biallelic cases reported with a renal phenotype (e.g. PMID: 23418020 - 3 patients with renal cysts and biallelic IFT140 variants, PMID: 27874174 - 1 patient with renal cysts and biallelic IFT140 variants) aswell as the monallelic variants reported in PMID:34890546
Cystic kidney disease v2.42 IFT140 Eleanor Williams Mode of inheritance for gene: IFT140 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1580 SCAF4 Ian Berry reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32730804; Phenotypes: Seizures, intellectual disability (mild); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.143 SOX11 Sarah Leigh edited their review of gene: SOX11: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. SOX11 variants have been reported by the NHS, including one from Tracy Lester and de novo variants in around 20 children with overlapping clinical features by Alisdair mcneill (Sheffield childrens hospital)(7 Oct 2019).; Changed rating: GREEN
Malformations of cortical development v2.143 SOX11 Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405).
Malformations of cortical development v2.143 SOX11 Sarah Leigh Phenotypes for gene: SOX11 were changed from intellectual disability; facial dysmorphism; microcephaly; digit anomalies; central nervous system malformations to Coffin-Siris syndrome 9, OMIM:615866
Intellectual disability v3.1580 SOX11 Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405).
Intellectual disability v3.1580 SOX11 Sarah Leigh Phenotypes for gene: SOX11 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 to Coffin-Siris syndrome 9, OMIM:615866
Intellectual disability v3.1579 SOX11 Sarah Leigh Publications for gene: SOX11 were set to 24886874
Malformations of cortical development v2.142 SOX11 Sarah Leigh Classified gene: SOX11 as Amber List (moderate evidence)
Malformations of cortical development v2.142 SOX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.142 SOX11 Sarah Leigh Gene: sox11 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.141 SOX11 Sarah Leigh Tag Q2_22_rating tag was added to gene: SOX11.
Tag Q2_22_NHS_review tag was added to gene: SOX11.
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh edited their review of gene: SLC5A6: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 6 variants have been reported in at least 4 unrelated cases. Supportive functional studies and targeted therapeutic interventionyielded clinical improvement in four of the five patients (PMID: 35013551).; Changed rating: GREEN; Changed publications to: 35013551; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Tag Q2_21_NHS_review tag was added to gene: SLC5A6.
Tag Q2_22_rating tag was added to gene: SLC5A6.
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.102 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to PMID: 35013551
Early onset or syndromic epilepsy v2.524 PRODH Sarah Leigh commented on gene: PRODH: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).