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Intellectual disability v3.448 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.447 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393
Intellectual disability v3.446 TRPM3 Arina Puzriakova Tag for-review tag was added to gene: TRPM3.
Intellectual disability v3.446 TRPM3 Arina Puzriakova reviewed gene: TRPM3: 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: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.27 DNMT3A Rachel Jones reviewed gene: DNMT3A: 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: PID: 30478443; Phenotypes: 618724 HEYN-SPROUL-JACKSON SYNDROME, HESJAS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 ZFYVE26 Zornitza Stark gene: ZFYVE26 was added
gene: ZFYVE26 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: ZFYVE26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE26 were set to 18394578; 14409555
Phenotypes for gene: ZFYVE26 were set to Spastic paraplegia 15, autosomal recessive MIM#270700
Review for gene: ZFYVE26 was set to GREEN
gene: ZFYVE26 was marked as current diagnostic
Added comment: Retinal degeneration can be a feature of this condition.
Sources: Expert list
Retinal disorders v2.20 WDPCP Zornitza Stark changed review comment from: Two families reported; the first one with a BBS phenotype, and in the second one affected individual had polysyndactyly and tongue hamartomas, so phenotype consistent with OFD rather than BBS. Note this gene has discordant ratings on multiple panels.; to: Four families reported, with different ciliopathy phenotypes including BBS, OFD and syndromic retinopathy.
Retinal disorders v2.20 WDPCP Zornitza Stark edited their review of gene: WDPCP: Changed rating: GREEN; Changed publications: 20671153, 25427950, 32055034, 29588463, 28289185
Retinal disorders v2.20 WDPCP Zornitza Stark reviewed gene: WDPCP: Rating: AMBER; Mode of pathogenicity: None; Publications: 20671153, 25427950; Phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD, Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 UNC119 Zornitza Stark reviewed gene: UNC119: Rating: GREEN; Mode of pathogenicity: None; Publications: 11006213, 23563732, 27079236; Phenotypes: Cone-rod dystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 TUBGCP6 Zornitza Stark reviewed gene: TUBGCP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22279524, 25344692; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 1, MIM# 251270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
IUGR and IGF abnormalities v1.33 RNPC3 Ivone Leong Classified gene: RNPC3 as Amber List (moderate evidence)
IUGR and IGF abnormalities v1.33 RNPC3 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber based on the evidence provided below.

Comments copied from Growth failure in early childhood (Version 1.13):
"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020"

"Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.

Zornitza Stark (Australian Genomics), 5 Oct 2020"
IUGR and IGF abnormalities v1.33 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
IUGR and IGF abnormalities v1.32 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160
IUGR and IGF abnormalities v1.31 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542
Retinal disorders v2.20 TUBGCP4 Zornitza Stark reviewed gene: TUBGCP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25817018, 32270730; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 3, MIM# 616335; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Retinal disorders v2.20 TUBB4B Zornitza Stark gene: TUBB4B was added
gene: TUBB4B was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TUBB4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB4B were set to 29198720
Phenotypes for gene: TUBB4B were set to Leber congenital amaurosis with early-onset deafness MIM#617879
Review for gene: TUBB4B was set to GREEN
gene: TUBB4B was marked as current diagnostic
Added comment: At least 5 affected individuals from 4 families with Leber congenital amaurosis and early-onset deafness with heterozygosity for 2 missense (R391H, R391C). Functional analysis demonstrated that the mutations have a significant dampening impact on microtubular growth.
Sources: Expert list
Retinal disorders v2.20 TRNT1 Zornitza Stark changed review comment from: The disorders associated with this gene likely represent a spectrum. RP/retinal dysfunction reported in more than 3 families, supportive functional data.; to: The disorders associated with this gene likely represent a spectrum rather than distinct conditions, therefore gene-disease association evidence assessed across publications. RP/retinal dysfunction reported in more than 3 families, supportive functional data.
Retinal disorders v2.20 TRNT1 Zornitza Stark reviewed gene: TRNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26494905, 28390992, 27389523; Phenotypes: Retinitis pigmentosa and erythrocytic microcytosis, MIM# 616959, Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, MIM# 616084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 TRIM32 Zornitza Stark reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: 16606853; Phenotypes: Bardet-Biedl syndrome 11, MIM# 615988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 TREX1 Zornitza Stark reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17660820; Phenotypes: Vasculopathy, retinal, with cerebral leukodystrophy, MIM# 192315; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 TRAF3IP1 Zornitza Stark gene: TRAF3IP1 was added
gene: TRAF3IP1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TRAF3IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAF3IP1 were set to 26487268
Phenotypes for gene: TRAF3IP1 were set to Senior-Loken syndrome 9, MIM#616629
Review for gene: TRAF3IP1 was set to GREEN
Added comment: At least 5 families reported with retinal degeneration as a feature of the condition and a zebrafish model with retinal degeneration.
Sources: Expert list
Retinal disorders v2.20 TMEM231 Zornitza Stark gene: TMEM231 was added
gene: TMEM231 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TMEM231 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM231 were set to 23012439; 27449316
Phenotypes for gene: TMEM231 were set to Joubert syndrome 20 MIM#614970
Review for gene: TMEM231 was set to GREEN
Added comment: Three unrelated families reported with retinopathy as a feature of the condition.
Sources: Expert list
Retinal disorders v2.20 TMEM216 Zornitza Stark reviewed gene: TMEM216: Rating: GREEN; Mode of pathogenicity: None; Publications: 32687549, 20512146; Phenotypes: Joubert syndrome 2, MIM# 608091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 SSBP1 Zornitza Stark gene: SSBP1 was added
gene: SSBP1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: SSBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SSBP1 were set to 31298765; 31479473; 31550237; 31550240
Phenotypes for gene: SSBP1 were set to Optic atrophy-13 with retinal and foveal abnormalities, MIM#165510
Review for gene: SSBP1 was set to GREEN
Added comment: At least 9 dominant families/cases and 1 recessive with optic atrophy with/without additional clinical features, including retinal macular dystrophy, sensorineural deafness, mitochondrial myopathy, and kidney failure. Supporting evidence in functional assays and zebrafish model.

Consider including here as well as the optic atrophy panel due to retinal features.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.335 ISCA-37433-Loss Eleanor Williams Publications for Region: ISCA-37433-Loss were set to 15889418; 20301696; 15545748
Primary immunodeficiency or monogenic inflammatory bowel disease v2.334 ISCA-37433-Loss Eleanor Williams edited their review of Region: ISCA-37433-Loss: Added comment: The following PubMed IDs were added to entity ISCA-37433-Loss: 12548732. These publications have been associated with OMIM phenotype MIM#188400, which is listed for this entity, by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 24198816, 20425828, 12548732
Primary immunodeficiency or monogenic inflammatory bowel disease v2.334 ISCA-37433-Loss Eleanor Williams reviewed Region: ISCA-37433-Loss: Rating: ; Mode of pathogenicity: None; Publications: 24198816, 20425828; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.334 ISCA-37446-Loss Eleanor Williams Publications for Region: ISCA-37446-Loss were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.333 ISCA-37446-Loss Eleanor Williams reviewed Region: ISCA-37446-Loss: Rating: ; Mode of pathogenicity: None; Publications: 12548732; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.333 ZAP70 Eleanor Williams Classified gene: ZAP70 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.333 ZAP70 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.333 ZAP70 Eleanor Williams Gene: zap70 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.332 XIAP Eleanor Williams Classified gene: XIAP as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.332 XIAP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.332 XIAP Eleanor Williams Gene: xiap has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.331 UNC13D Eleanor Williams Classified gene: UNC13D as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.331 UNC13D Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.331 UNC13D Eleanor Williams Gene: unc13d has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.330 TTC7A Eleanor Williams Classified gene: TTC7A as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.330 TTC7A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.330 TTC7A Eleanor Williams Gene: ttc7a has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.329 TREX1 Eleanor Williams Classified gene: TREX1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.329 TREX1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.329 TREX1 Eleanor Williams Gene: trex1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.328 TRAC Eleanor Williams Classified gene: TRAC as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.328 TRAC Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.328 TRAC Eleanor Williams Gene: trac has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.327 TPP2 Eleanor Williams Classified gene: TPP2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.327 TPP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.327 TPP2 Eleanor Williams Gene: tpp2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.326 TNFRSF1A Eleanor Williams Classified gene: TNFRSF1A as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.326 TNFRSF1A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.326 TNFRSF1A Eleanor Williams Gene: tnfrsf1a has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.325 TNFAIP3 Eleanor Williams Classified gene: TNFAIP3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.325 TNFAIP3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.325 TNFAIP3 Eleanor Williams Gene: tnfaip3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.324 TMEM173 Eleanor Williams Classified gene: TMEM173 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.324 TMEM173 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.324 TMEM173 Eleanor Williams Gene: tmem173 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.323 TCN2 Eleanor Williams Classified gene: TCN2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.323 TCN2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.323 TCN2 Eleanor Williams Gene: tcn2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.322 TAP2 Eleanor Williams Classified gene: TAP2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.322 TAP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.322 TAP2 Eleanor Williams Gene: tap2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.321 TAP1 Eleanor Williams Classified gene: TAP1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.321 TAP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.321 TAP1 Eleanor Williams Gene: tap1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.320 STXBP2 Eleanor Williams Classified gene: STXBP2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.320 STXBP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.320 STXBP2 Eleanor Williams Gene: stxbp2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.319 STXBP2 Eleanor Williams Classified gene: STXBP2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.319 STXBP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.319 STXBP2 Eleanor Williams Gene: stxbp2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.318 STX11 Eleanor Williams Classified gene: STX11 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.318 STX11 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.318 STX11 Eleanor Williams Gene: stx11 has been classified as Green List (High Evidence).
DDG2P v2.10 RINT1 Dmitrijs Rots Deleted their review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.317 STK4 Eleanor Williams Classified gene: STK4 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.317 STK4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.317 STK4 Eleanor Williams Gene: stk4 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.316 STIM1 Eleanor Williams Classified gene: STIM1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.316 STIM1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.316 STIM1 Eleanor Williams Gene: stim1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.315 STAT5B Eleanor Williams Classified gene: STAT5B as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.315 STAT5B Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.315 STAT5B Eleanor Williams Gene: stat5b has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.314 STAT3 Eleanor Williams Classified gene: STAT3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.314 STAT3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.314 STAT3 Eleanor Williams Gene: stat3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.313 SP110 Eleanor Williams Classified gene: SP110 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.313 SP110 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.313 SP110 Eleanor Williams Gene: sp110 has been classified as Green List (High Evidence).
Skeletal dysplasia v2.22 RINT1 Dmitrijs Rots gene: RINT1 was added
gene: RINT1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to PMID: 31204009
Phenotypes for gene: RINT1 were set to liver failure; short stature; skeletal abnormalities
Penetrance for gene: RINT1 were set to Complete
Review for gene: RINT1 was set to GREEN
gene: RINT1 was marked as current diagnostic
Added comment: Reported in 3 patients with similar phenotype in PMID: 31204009. Caused by one LoF allele and missense/in-frame hypomorphic allele.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.312 SMARCAL1 Eleanor Williams Classified gene: SMARCAL1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.312 SMARCAL1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.312 SMARCAL1 Eleanor Williams Gene: smarcal1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.311 SLC46A1 Eleanor Williams Classified gene: SLC46A1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.311 SLC46A1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.311 SLC46A1 Eleanor Williams Gene: slc46a1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.310 SLC29A3 Eleanor Williams Classified gene: SLC29A3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.310 SLC29A3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.310 SLC29A3 Eleanor Williams Gene: slc29a3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.309 SH2D1A Eleanor Williams Classified gene: SH2D1A as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.309 SH2D1A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.309 SH2D1A Eleanor Williams Gene: sh2d1a has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.308 RMRP Eleanor Williams Classified gene: RMRP as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.308 RMRP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.308 RMRP Eleanor Williams Gene: rmrp has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.307 RFXAP Eleanor Williams Classified gene: RFXAP as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.307 RFXAP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.307 RFXAP Eleanor Williams Gene: rfxap has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.306 RFXANK Eleanor Williams Classified gene: RFXANK as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.306 RFXANK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.306 RFXANK Eleanor Williams Gene: rfxank has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.305 RFX5 Eleanor Williams Classified gene: RFX5 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.305 RFX5 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.305 RFX5 Eleanor Williams Gene: rfx5 has been classified as Green List (High Evidence).
DDG2P v2.10 RINT1 Dmitrijs Rots reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31204009; Phenotypes: liver failure, short stature, skeletal abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.304 RBCK1 Eleanor Williams Classified gene: RBCK1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.304 RBCK1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.304 RBCK1 Eleanor Williams Gene: rbck1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.303 RASGRP1 Eleanor Williams Classified gene: RASGRP1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.303 RASGRP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.303 RASGRP1 Eleanor Williams Gene: rasgrp1 has been classified as Green List (High Evidence).
Intellectual disability v3.446 FGF14 Arina Puzriakova Classified gene: FGF14 as Amber List (moderate evidence)
Intellectual disability v3.446 FGF14 Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment has been reported in several patients, mostly mild but few cases with moderate deficits have also been described. However, the phenotype is mainly characterised by ataxia which would be the expected CI for diagnostic testing - FGF14 is already Green on Ataxia panels.

The utility of calling variants in this gene in a cohort of ID patients without the ataxic component is unlikely to be of benefit, and therefore the rating has been kept Amber on this panel.
Intellectual disability v3.446 FGF14 Arina Puzriakova Gene: fgf14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.445 FGF14 Arina Puzriakova Publications for gene: FGF14 were set to 15470364
Primary immunodeficiency or monogenic inflammatory bowel disease v2.302 RAG2 Eleanor Williams Classified gene: RAG2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.302 RAG2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.302 RAG2 Eleanor Williams Gene: rag2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.301 RAG1 Eleanor Williams Classified gene: RAG1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.301 RAG1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.301 RAG1 Eleanor Williams Gene: rag1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.300 RAB27A Eleanor Williams Classified gene: RAB27A as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.300 RAB27A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.300 RAB27A Eleanor Williams Gene: rab27a has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.299 PTPRC Eleanor Williams Classified gene: PTPRC as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.299 PTPRC Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.299 PTPRC Eleanor Williams Gene: ptprc has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.298 PSTPIP1 Eleanor Williams Classified gene: PSTPIP1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.298 PSTPIP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.298 PSTPIP1 Eleanor Williams Gene: pstpip1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.297 PSMB8 Eleanor Williams Classified gene: PSMB8 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.297 PSMB8 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.297 PSMB8 Eleanor Williams Gene: psmb8 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.296 PRKCD Eleanor Williams Classified gene: PRKCD as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.296 PRKCD Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.296 PRKCD Eleanor Williams Gene: prkcd has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.295 PRF1 Eleanor Williams Classified gene: PRF1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.295 PRF1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.295 PRF1 Eleanor Williams Gene: prf1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.294 POLA1 Eleanor Williams Classified gene: POLA1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.294 POLA1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.294 POLA1 Eleanor Williams Gene: pola1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.293 PNP Eleanor Williams Classified gene: PNP as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.293 PNP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.293 PNP Eleanor Williams Gene: pnp has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.292 PLCG2 Eleanor Williams Classified gene: PLCG2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.292 PLCG2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.292 PLCG2 Eleanor Williams Gene: plcg2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.291 PEPD Eleanor Williams Classified gene: PEPD as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.291 PEPD Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.291 PEPD Eleanor Williams Gene: pepd has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.290 OTULIN Eleanor Williams Classified gene: OTULIN as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.290 OTULIN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.290 OTULIN Eleanor Williams Gene: otulin has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.289 ORAI1 Eleanor Williams Classified gene: ORAI1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.289 ORAI1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.289 ORAI1 Eleanor Williams Gene: orai1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.288 NOD2 Eleanor Williams Classified gene: NOD2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.288 NOD2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.288 NOD2 Eleanor Williams Gene: nod2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.287 NLRP3 Eleanor Williams Classified gene: NLRP3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.287 NLRP3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.287 NLRP3 Eleanor Williams Gene: nlrp3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.286 NLRP12 Eleanor Williams Classified gene: NLRP12 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.286 NLRP12 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.286 NLRP12 Eleanor Williams Gene: nlrp12 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.285 NLRC4 Eleanor Williams Classified gene: NLRC4 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.285 NLRC4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.285 NLRC4 Eleanor Williams Gene: nlrc4 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.284 NHEJ1 Eleanor Williams Classified gene: NHEJ1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.284 NHEJ1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.284 NHEJ1 Eleanor Williams Gene: nhej1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.283 NFKBIA Eleanor Williams Classified gene: NFKBIA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.283 NFKBIA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.283 NFKBIA Eleanor Williams Gene: nfkbia has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.282 MYSM1 Eleanor Williams Classified gene: MYSM1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.282 MYSM1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.282 MYSM1 Eleanor Williams Gene: mysm1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.281 MVK Eleanor Williams Classified gene: MVK as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.281 MVK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.281 MVK Eleanor Williams Gene: mvk has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.280 MTHFD1 Eleanor Williams Classified gene: MTHFD1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.280 MTHFD1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.280 MTHFD1 Eleanor Williams Gene: mthfd1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.279 MSN Eleanor Williams Classified gene: MSN as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.279 MSN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.279 MSN Eleanor Williams Gene: msn has been classified as Green List (High Evidence).
Inherited ovarian cancer (without breast cancer) v2.3 PALB2 marc tischkowitz reviewed gene: PALB2: 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: 31841383: PMID: 32546565; Phenotypes: breast cancer, ovarian cancer, pancreatic cancer; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.278 MEFV Eleanor Williams Classified gene: MEFV as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.278 MEFV Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.278 MEFV Eleanor Williams Gene: mefv has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.277 MAP3K14 Eleanor Williams Classified gene: MAP3K14 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.277 MAP3K14 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.277 MAP3K14 Eleanor Williams Gene: map3k14 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.276 MALT1 Eleanor Williams Classified gene: MALT1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.276 MALT1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.276 MALT1 Eleanor Williams Gene: malt1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.275 MAGT1 Eleanor Williams Classified gene: MAGT1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.275 MAGT1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.275 MAGT1 Eleanor Williams Gene: magt1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.274 LYST Eleanor Williams Classified gene: LYST as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.274 LYST Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.274 LYST Eleanor Williams Gene: lyst has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.273 LRBA Eleanor Williams Classified gene: LRBA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.273 LRBA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.273 LRBA Eleanor Williams Gene: lrba has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.272 LPIN2 Eleanor Williams Classified gene: LPIN2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.272 LPIN2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.272 LPIN2 Eleanor Williams Gene: lpin2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.271 LIG4 Eleanor Williams Classified gene: LIG4 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.271 LIG4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.271 LIG4 Eleanor Williams Gene: lig4 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.270 LCK Eleanor Williams Classified gene: LCK as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.270 LCK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.270 LCK Eleanor Williams Gene: lck has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.269 LAT Eleanor Williams Classified gene: LAT as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.269 LAT Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.269 LAT Eleanor Williams Gene: lat has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.268 JAK3 Eleanor Williams Classified gene: JAK3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.268 JAK3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.268 JAK3 Eleanor Williams Gene: jak3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.267 ITK Eleanor Williams Classified gene: ITK as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.267 ITK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.267 ITK Eleanor Williams Gene: itk has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.266 ITCH Eleanor Williams Classified gene: ITCH as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.266 ITCH Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.266 ITCH Eleanor Williams Gene: itch has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.265 IL7R Eleanor Williams Classified gene: IL7R as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.265 IL7R Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.265 IL7R Eleanor Williams Gene: il7r has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.264 IL36RN Eleanor Williams Classified gene: IL36RN as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.264 IL36RN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.264 IL36RN Eleanor Williams Gene: il36rn has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.263 IL2RG Eleanor Williams Classified gene: IL2RG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.263 IL2RG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.263 IL2RG Eleanor Williams Gene: il2rg has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.262 IL2RA Eleanor Williams Classified gene: IL2RA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.262 IL2RA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.262 IL2RA Eleanor Williams Gene: il2ra has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.261 IL21R Eleanor Williams Classified gene: IL21R as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.261 IL21R Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.261 IL21R Eleanor Williams Gene: il21r has been classified as Green List (High Evidence).
Intellectual disability v3.444 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Early onset or syndromic epilepsy v2.172 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Intellectual disability v3.443 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Classified gene: FDFT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Added comment: Comment on list classification: Expert review on FDFT1 following a publication by Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

FDFT1 is in OMIM based on this paper. As there are only two families classifying FDFT1 as Amber until more evidence is available (added 'watchlist' tag).
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Gene: fdft1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.260 IL1RN Eleanor Williams Classified gene: IL1RN as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.260 IL1RN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.260 IL1RN Eleanor Williams Gene: il1rn has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.259 IL10RB Eleanor Williams Classified gene: IL10RB as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.259 IL10RB Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.259 IL10RB Eleanor Williams Gene: il10rb has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.258 IL10RA Eleanor Williams Classified gene: IL10RA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.258 IL10RA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.258 IL10RA Eleanor Williams Gene: il10ra has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.257 IL10 Eleanor Williams Classified gene: IL10 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.257 IL10 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.257 IL10 Eleanor Williams Gene: il10 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.256 IKBKG Eleanor Williams Classified gene: IKBKG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.256 IKBKG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.256 IKBKG Eleanor Williams Gene: ikbkg has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.255 IKBKB Eleanor Williams Classified gene: IKBKB as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.255 IKBKB Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.255 IKBKB Eleanor Williams Gene: ikbkb has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.254 ICOS Eleanor Williams Classified gene: ICOS as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.254 ICOS Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.254 ICOS Eleanor Williams Gene: icos has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.253 FOXP3 Eleanor Williams Classified gene: FOXP3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.253 FOXP3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.253 FOXP3 Eleanor Williams Gene: foxp3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.252 FOXN1 Eleanor Williams Classified gene: FOXN1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.252 FOXN1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.252 FOXN1 Eleanor Williams Gene: foxn1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.251 FAT4 Eleanor Williams Classified gene: FAT4 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.251 FAT4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.251 FAT4 Eleanor Williams Gene: fat4 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.250 FASLG Eleanor Williams Classified gene: FASLG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.250 FASLG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.250 FASLG Eleanor Williams Gene: faslg has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.249 FAS Eleanor Williams Classified gene: FAS as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.249 FAS Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.249 FAS Eleanor Williams Gene: fas has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.248 FADD Eleanor Williams Classified gene: FADD as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.248 FADD Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.248 FADD Eleanor Williams Gene: fadd has been classified as Green List (High Evidence).
Intellectual disability v3.443 DENND5A Arina Puzriakova Phenotypes for gene: DENND5A were changed from EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 49 617281
Primary immunodeficiency or monogenic inflammatory bowel disease v2.247 EXTL3 Eleanor Williams Classified gene: EXTL3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.247 EXTL3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.247 EXTL3 Eleanor Williams Gene: extl3 has been classified as Green List (High Evidence).
Intellectual disability v3.442 DENND5A Arina Puzriakova Classified gene: DENND5A as Amber List (moderate evidence)
Intellectual disability v3.442 DENND5A Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as disorder is mainly characterised by severe early-infantile encephalopathy, and cognitive arrest appears secondary to the onset of seizures.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting cases.
Intellectual disability v3.442 DENND5A Arina Puzriakova Gene: dennd5a has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.246 EPG5 Eleanor Williams Classified gene: EPG5 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.246 EPG5 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.246 EPG5 Eleanor Williams Gene: epg5 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.245 DOCK8 Eleanor Williams Classified gene: DOCK8 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.245 DOCK8 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.245 DOCK8 Eleanor Williams Gene: dock8 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.244 DOCK2 Eleanor Williams Classified gene: DOCK2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.244 DOCK2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.244 DOCK2 Eleanor Williams Gene: dock2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.243 DCLRE1C Eleanor Williams Classified gene: DCLRE1C as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.243 DCLRE1C Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.243 DCLRE1C Eleanor Williams Gene: dclre1c has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.242 CTPS1 Eleanor Williams Classified gene: CTPS1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.242 CTPS1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.242 CTPS1 Eleanor Williams Gene: ctps1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.241 CTLA4 Eleanor Williams Classified gene: CTLA4 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.241 CTLA4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.241 CTLA4 Eleanor Williams Gene: ctla4 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.240 CORO1A Eleanor Williams Classified gene: CORO1A as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.240 CORO1A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.240 CORO1A Eleanor Williams Gene: coro1a has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.239 COPA Eleanor Williams Classified gene: COPA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.239 COPA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.239 COPA Eleanor Williams Gene: copa has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.238 CIITA Eleanor Williams Classified gene: CIITA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.238 CIITA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.238 CIITA Eleanor Williams Gene: ciita has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.237 CD70 Eleanor Williams Classified gene: CD70 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.237 CD70 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.237 CD70 Eleanor Williams Gene: cd70 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.236 CD40LG Eleanor Williams Classified gene: CD40LG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.236 CD40LG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.236 CD40LG Eleanor Williams Gene: cd40lg has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.235 CD40 Eleanor Williams Classified gene: CD40 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.235 CD40 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.235 CD40 Eleanor Williams Gene: cd40 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.234 CD3G Eleanor Williams Classified gene: CD3G as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.234 CD3G Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.234 CD3G Eleanor Williams Gene: cd3g has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.233 CD3E Eleanor Williams Classified gene: CD3E as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.233 CD3E Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.233 CD3E Eleanor Williams Gene: cd3e has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.232 CD3D Eleanor Williams Classified gene: CD3D as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.232 CD3D Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.232 CD3D Eleanor Williams Gene: cd3d has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.231 CD27 Eleanor Williams Classified gene: CD27 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.231 CD27 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.231 CD27 Eleanor Williams Gene: cd27 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.230 CCBE1 Eleanor Williams Classified gene: CCBE1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.230 CCBE1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.230 CCBE1 Eleanor Williams Gene: ccbe1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.229 CASP8 Eleanor Williams Classified gene: CASP8 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.229 CASP8 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.229 CASP8 Eleanor Williams Gene: casp8 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.228 CASP10 Eleanor Williams Classified gene: CASP10 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.228 CASP10 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.228 CASP10 Eleanor Williams Gene: casp10 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.227 CARMIL2 Eleanor Williams Classified gene: CARMIL2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.227 CARMIL2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.227 CARMIL2 Eleanor Williams Gene: carmil2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.226 CARD14 Eleanor Williams Classified gene: CARD14 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.226 CARD14 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.226 CARD14 Eleanor Williams Gene: card14 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.225 CARD11 Eleanor Williams Classified gene: CARD11 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.225 CARD11 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.225 CARD11 Eleanor Williams Gene: card11 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.224 BACH2 Eleanor Williams Classified gene: BACH2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.224 BACH2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.224 BACH2 Eleanor Williams Gene: bach2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.223 B2M Eleanor Williams Classified gene: B2M as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.223 B2M Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.223 B2M Eleanor Williams Gene: b2m has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.222 AP3B1 Eleanor Williams Classified gene: AP3B1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.222 AP3B1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.222 AP3B1 Eleanor Williams Gene: ap3b1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.221 AK2 Eleanor Williams Classified gene: AK2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.221 AK2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.221 AK2 Eleanor Williams Gene: ak2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.220 AIRE Eleanor Williams Classified gene: AIRE as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.220 AIRE Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.220 AIRE Eleanor Williams Gene: aire has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.219 ADA2 Eleanor Williams Classified gene: ADA2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.219 ADA2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.219 ADA2 Eleanor Williams Gene: ada2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.218 ADA Eleanor Williams Classified gene: ADA as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.218 ADA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.218 ADA Eleanor Williams Gene: ada has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.217 ACP5 Eleanor Williams Classified gene: ACP5 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.217 ACP5 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.217 ACP5 Eleanor Williams Gene: acp5 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.216 TBX1 Eleanor Williams Classified gene: TBX1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.216 TBX1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.216 TBX1 Eleanor Williams Gene: tbx1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.215 TAPBP Eleanor Williams Classified gene: TAPBP as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.215 TAPBP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.215 TAPBP Eleanor Williams Gene: tapbp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.214 RHOH Eleanor Williams Classified gene: RHOH as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.214 RHOH Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.214 RHOH Eleanor Williams Gene: rhoh has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.213 NLRP1 Eleanor Williams Classified gene: NLRP1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.213 NLRP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.213 NLRP1 Eleanor Williams Gene: nlrp1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.212 IL21 Eleanor Williams Classified gene: IL21 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.212 IL21 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.212 IL21 Eleanor Williams Gene: il21 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.211 CD8A Eleanor Williams Classified gene: CD8A as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.211 CD8A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.211 CD8A Eleanor Williams Gene: cd8a has been classified as Amber List (Moderate Evidence).
DDG2P v2.10 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME 614615 to Joubert syndrome 25, 616781
Fetal anomalies v1.105 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME to Joubert syndrome 25, 616781
Primary immunodeficiency or monogenic inflammatory bowel disease v2.210 AP1S3 Eleanor Williams Classified gene: AP1S3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.210 AP1S3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.210 AP1S3 Eleanor Williams Gene: ap1s3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.441 CEP104 Arina Puzriakova changed review comment from: Four related cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.; to: Four unrelated cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.
Intellectual disability v3.441 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME to Joubert syndrome 25, 616781
Intellectual disability v3.440 CEP104 Arina Puzriakova Publications for gene: CEP104 were set to
Intellectual disability v3.439 CEP104 Arina Puzriakova Classified gene: CEP104 as Amber List (moderate evidence)
Intellectual disability v3.439 CEP104 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support a Green rating on this panel, and so this gene will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.439 CEP104 Arina Puzriakova Gene: cep104 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.438 CEP104 Arina Puzriakova Tag for-review tag was added to gene: CEP104.
Intellectual disability v3.438 CEP104 Arina Puzriakova edited their review of gene: CEP104: Added comment: Four related cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.; Changed publications: 26477546, 31625690
Intellectual disability v3.438 CEP104 Arina Puzriakova reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 31625690; Phenotypes: Joubert syndrome 25, 616781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.39 MPV17 Ivone Leong Phenotypes for gene: MPV17 were changed from Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), MIM# 256810 to Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), 256810
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Tag for-review tag was added to gene: OCRL.
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Classified gene: OCRL as Amber List (moderate evidence)
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is even evidence to support a gene-disease assocation and therefore this gene should be rated Green for this panel. It has been given an Amber rating for now until the next major review of this panel.
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Gene: ocrl has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Classified gene: CACNA2D2 as Amber List (moderate evidence)
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as severe GDD is a neurodegenerative manifestation that is secondary to the onset of seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Gene: cacna2d2 has been classified as Amber List (Moderate Evidence).
Hypophosphataemia or rickets v2.9 OCRL Ivone Leong Phenotypes for gene: OCRL were changed from Lowe syndrome, MIM# 309000 to Lowe syndrome, 309000
Hypertrophic cardiomyopathy v2.11 JPH2 Zornitza Stark reviewed gene: JPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30681346, 17509612, 23973696, 26869393, 28393127, 30235249; Phenotypes: Cardiomyopathy, hypertrophic, MIM#613873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 RIMS2 Zornitza Stark gene: RIMS2 was added
gene: RIMS2 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: RIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIMS2 were set to 32470375
Phenotypes for gene: RIMS2 were set to Cone-rod synaptic disorder syndrome, congenital nonprogressive, MIM# 618970
Review for gene: RIMS2 was set to GREEN
gene: RIMS2 was marked as current diagnostic
Added comment: Biallelic LoF variants reported with syndromic congenital cone-rod synaptic disease in 7 individuals from 4 families.
Sources: Expert list
Retinal disorders v2.20 RDH11 Zornitza Stark reviewed gene: RDH11: Rating: RED; Mode of pathogenicity: None; Publications: 24916380, 15634683, 30731079, 18326732; Phenotypes: Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.437 CARS2 Arina Puzriakova Publications for gene: CARS2 were set to 25787132
Intellectual disability v3.436 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Intellectual disability v3.436 CARS2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.436 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Classified gene: C2CD3 as Amber List (moderate evidence)
Intellectual disability v3.435 C2CD3 Arina Puzriakova Added comment: Comment on list classification: Despite phenotypic diversity among cases with C2CD3 variants, ID/DD is consistently reported in living patients.

Therefore, this gene could be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Gene: c2cd3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.434 C2CD3 Arina Puzriakova Phenotypes for gene: C2CD3 were changed from ?Orofaciodigital syndrome XIV 615948 to Orofaciodigital syndrome XIV, 615948; Joubert-related disorder
Intellectual disability v3.433 C2CD3 Arina Puzriakova Publications for gene: C2CD3 were set to 27094867; 24997988
Intellectual disability v3.432 C2CD3 Arina Puzriakova Tag for-review tag was added to gene: C2CD3.
Intellectual disability v3.432 C2CD3 Arina Puzriakova edited their review of gene: C2CD3: Changed publications: 24997988, 26092869, 26477546, 27094867, 30097616
Intellectual disability v3.432 C2CD3 Arina Puzriakova changed review comment from: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with occipital encephalocele and a ventricular septal defect. Similar abnormalities were identified in another sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.; to: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.
Intellectual disability v3.432 C2CD3 Arina Puzriakova reviewed gene: C2CD3: Rating: ; Mode of pathogenicity: None; Publications: 24997988, 26092869, 26477546, 27094867; Phenotypes: Orofaciodigital syndrome XIV, 615948, Joubert-related disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypophosphataemia or rickets v2.8 FAH Ivone Leong Phenotypes for gene: FAH were changed from Tyrosinemia, type I, MIM# 276700 to Tyrosinemia, type I, 276700
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SH3BP2 Eleanor Williams Source Other was added to SH3BP2.
Publications for gene SH3BP2 were updated from 29669173; 22640988; 32048120; 28914985; 11381256; 32086639; 25705883; 25470448; 25220465 to 25220465; 11381256; 25705883; 25470448; 32048120; 32086639; 29669173; 11113824; 22640988; 28914985; 16053841
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TFRC Eleanor Williams Source Other was added to TFRC.
Publications for gene TFRC were updated from 32048120; 32086639; 26642240 to 32086639; 26642240; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TBX1 Eleanor Williams Source Other was added to TBX1.
Publications for gene TBX1 were updated from 11242110; 14585638; 24198816; 32048120; 32086639 to 11242110; 32048120; 32086639; 14585638; 24198816; 12548732
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRP1 Eleanor Williams Source Other was added to NLRP1.
Publications for gene NLRP1 were updated from 29850521; 27662089; 31484767; 27965258 to 27965258; 31484767; 27662089; 29850521
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL21 Eleanor Williams Source Other was added to IL21.
Publications for gene IL21 were updated from 32048120; 24746753; 32086639 to 32086639; 24746753; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 BCL11B Eleanor Williams Publications for gene BCL11B were updated from 27959755; 32086639; 29296816; 32048120 to 27959755; 32086639; 29296816; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 AP1S3 Eleanor Williams Source Other was added to AP1S3.
Publications for gene AP1S3 were updated from 32048120; 32086639 to 32086639; 24791904; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 XIAP Eleanor Williams Source Other was added to XIAP.
Publications for gene XIAP were updated from 17080092; 21119115; 25943627; 21173700; 22228567 to 26581487; 21119115; 23973892; 17080092; 21173700; 22228567; 23131490; 25943627; 31754776
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 UNC13D Eleanor Williams Source Other was added to UNC13D.
Publications for gene UNC13D were updated from 14622600; 16278825; 15632205; 17993578; 15703195 to 15703195; 16278825; 17993578; 27914778; 15632205; 14622600; 29312353
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TREX1 Eleanor Williams Source Other was added to TREX1.
Publications for gene TREX1 were updated from 20799324; 16845398; 21808053; 25604658 to 16845398; 25604658; 21808053; 17846997; 20799324
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TRAC Eleanor Williams Source Other was added to TRAC.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TNFRSF1A Eleanor Williams Source Other was added to TNFRSF1A.
Publications for gene TNFRSF1A were updated from 10199409; 11175303; 10902757; 17360963 to 10199409; 12209523; 11175303; 10902757; 23965844; 17360963; 11115159
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TNFAIP3 Eleanor Williams Source Other was added to TNFAIP3.
Publications for gene TNFAIP3 were updated from 26642243; 27845235; 29572183; 28659290; 29317407 to 31164164; 29317407; 26642243; 28659290; 27845235; 29572183
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TMEM173 Eleanor Williams Source Other was added to TMEM173.
Publications for gene TMEM173 were updated from 25029335; 25401470; 30705050; 29976662; 29491158; 29425920 to 25401470; 29425920; 25029335; 29491158; 29976662; 30705050
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STXBP2 Eleanor Williams Source Other was added to STXBP2.
Publications for gene STXBP2 were updated from 19804848; 19884660; 20798128; 20301617 to 19884660; 30557712; 29776323; 22451424; 20798128; 20301617; 19804848
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STX11 Eleanor Williams Source Other was added to STX11.
Publications for gene STX11 were updated from 15703195; 16278825; 16582076; 24459464; 20301617 to 16278825; 18710388; 16582076; 20301617; 24459464; 15703195
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STK4 Eleanor Williams Source Other was added to STK4.
Publications for gene STK4 were updated from 22174160; 22294732; 26801501; 26117625; 24453252 to 22294732; 26801501; 24453252; 26117625; 22174160
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STAT3 Eleanor Williams Source Other was added to STAT3.
Publications for gene STAT3 were updated from 17676033; 17881745; 25038750; 25359994 to 28402852; 25349174; 17881745; 17676033; 25359994; 25038750
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SLC29A3 Eleanor Williams Source Other was added to SLC29A3.
Publications for gene SLC29A3 were updated from 16650224; 18940313; 20619369; 17461801; 19336477; 16155931; 20140240; 16118898; 21178579; 19175903; 9545394; 21888995; 23530176; 18947330; 22238637; 22653152; 22875837 to 17461801; 19336477; 23530176; 18940313; 22238637; 16118898; 22875837; 19175903; 21888995; 20140240; 16155931; 21178579; 9545394; 16650224; 22653152; 18947330; 20619369
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SH2D1A Eleanor Williams Source Other was added to SH2D1A.
Publications for gene SH2D1A were updated from 9771704; 10556288; 10598819; 10694488; 11049992; 29670631; 9774102 to 21119115; 29670631; 10556288; 9774102; 11049992; 10598819; 9771704; 10694488; 25085526; 31754776
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PSTPIP1 Eleanor Williams Source Other was added to PSTPIP1.
Publications for gene PSTPIP1 were updated from 28251506; 28628471; 28960754; 29575118; 26025129 to 21532836; 9212761; 28628471; 28251506; 28960754; 22161697; 26025129; 29575118
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PRF1 Eleanor Williams Source Other was added to PRF1.
Publications for gene PRF1 were updated from 11179007; 10583959; 12229880; 14757862; 20301617; 15365097; 15632205; 14757862; 16860143 to 28468610; 22248322; 12229880; 28806468; 15365097; 11179007; 14757862; 16860143; 10583959; 15632205; 20301617
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 POLA1 Eleanor Williams Source Other was added to POLA1.
Publications for gene POLA1 were updated from 27019227 to 27019227; 6794369; 15804299
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PLCG2 Eleanor Williams Source Other was added to PLCG2.
Publications for gene PLCG2 were updated from 22236196; 23000145; 29538758 to 23000145; 29538758; 25760457; 22236196
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 OTULIN Eleanor Williams Source Other was added to OTULIN.
Publications for gene OTULIN were updated from 27523608; 27559085 to 27559085; 27523608
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NOD2 Eleanor Williams Source Other was added to NOD2.
Publications for gene NOD2 were updated from 11528384; 18955195; 15459013; 4056967 to 11528384; 25416713; 4056967; 25136265; 15459013; 19479837; 18955195; 28887115
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRP3 Eleanor Williams Publications for gene NLRP3 were updated from 28847925; 12522564; 11590390; 14872505; 14476827; 29366613; 11992256; 12032915; 11687797 to 28847925; 12522564; 11590390; 14872505; 18423104; 14476827; 29366613; 11992256; 12032915; 11687797
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRP3 Eleanor Williams Publications for gene NLRP3 were updated from 28847925; 12522564; 29366613; 11992256; 12032915; 11687797 to 28847925; 12522564; 11590390; 14872505; 14476827; 29366613; 11992256; 12032915; 11687797
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRP3 Eleanor Williams Source Other was added to NLRP3.
Publications for gene NLRP3 were updated from 11687797; 11992256; 12032915; 12522564; 28847925; 29366613 to 28847925; 12522564; 29366613; 11992256; 12032915; 11687797
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRP12 Eleanor Williams Source Other was added to NLRP12.
Publications for gene NLRP12 were updated from 18230725; 27779193; 27633793; 29178652; 29248470 to 18230725; 27633793; 29178652; 21360512; 27779193; 29248470
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRC4 Eleanor Williams Publications for gene NLRC4 were updated from 27876626; 25217959; 25385754; 25217960 to 27876626; 25217959; 25385754; 25217960
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NLRC4 Eleanor Williams Source Other was added to NLRC4.
Publications for gene NLRC4 were updated from 25217960; 25217959; 25385754; 27876626 to 27876626; 25217959; 25385754; 25217960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MVK Eleanor Williams Source Other was added to MVK.
Publications for gene MVK were updated from 10369261; 16435210 to 19011501; 16435210; 22038276; 21708801; 10369261
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MSN Eleanor Williams Source Other was added to MSN.
Publications for gene MSN were updated from 27405666; 29556235 to 29556235; 27405666
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MEFV Eleanor Williams Publications for gene MEFV were updated from 9288094; 9668175; 14679589; 10090880; 9266193; 10787449; 11903360; 15643295; 11242116 to 9288094; 9668175; 14679589; 10090880; 9266193; 10787449; 11903360; 15643295; 11242116
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MEFV Eleanor Williams Source Other was added to MEFV.
Publications for gene MEFV were updated from 14679589; 10787449; 11903360; 11242116; 10090880; 9668175; 9288094 to 9288094; 9668175; 14679589; 10090880; 9266193; 10787449; 11903360; 15643295; 11242116
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MALT1 Eleanor Williams Source Other was added to MALT1.
Publications for gene MALT1 were updated from 23727036; 24332264; 25627829 to 25627829; 23727036; 24332264
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MAGT1 Eleanor Williams Source Other was added to MAGT1.
Publications for gene MAGT1 were updated from 21796205; 23846901; 27095930; 25956530; 25504528; 25205404; 24550228; 23871722; 21983175 to 25205404; 27095930; 25956530; 23846901; 21796205; 25504528; 29635109; 23871722; 21983175; 24550228
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LYST Eleanor Williams Source Other was added to LYST.
Publications for gene LYST were updated from 8896560; 9215679; 9215680; 10482950 to 9215679; 18043242; 8717042; 9215680; 10482950; 8896560; 26944273; 29939658
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LRBA Eleanor Williams Source Other was added to LRBA.
Publications for gene LRBA were updated from 22608502; 25468195; 22721650 to 26768763; 25468195; 25931386; 22608502; 22721650; 26707784
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LPIN2 Eleanor Williams Source Other was added to LPIN2.
Publications for gene LPIN2 were updated from 29387759; 15994876; 17330256; 27860302 to 2809904; 27252506; 29387759; 10969284; 17330256; 15994876; 27860302
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LCK Eleanor Williams Source Other was added to LCK.
Publications for gene LCK were updated from 22985903; 9664084; 11351273 to 22985903; 11351273; 9664084
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL36RN Eleanor Williams Source Other was added to IL36RN.
Publications for gene IL36RN were updated from 23303454; 23698098; 22903787 to 23303454; 21848462; 23698098; 22903787; 21839423
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL2RA Eleanor Williams Source Other was added to IL2RA.
Publications for gene IL2RA were updated from 9096364; 17196245; 23416241; 24116927 to 9096364; 24116927; 17196245; 23416241
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL21R Eleanor Williams Source Other was added to IL21R.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL1RN Eleanor Williams Source Other was added to IL1RN.
Publications for gene IL1RN were updated from 19494218; 19494219 to 19494219; 22127713; 19494218
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL10RB Eleanor Williams Source Other was added to IL10RB.
Publications for gene IL10RB were updated from 19890111; 21519361; 28785144; 27350736; 27302973 to 22236434; 27350736; 27302973; 19890111; 21519361; 28785144
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL10RA Eleanor Williams Source Other was added to IL10RA.
Publications for gene IL10RA were updated from 19890111; 21519361; 22476154; 29788474; 29248579; 29140941; 28864178; 29059189 to 22476154; 29248579; 19890111; 21519361; 29059189; 29140941; 28864178; 22236434; 29788474
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FOXP3 Eleanor Williams Source Other was added to FOXP3.
Publications for gene FOXP3 were updated from 17635943; 16741580; 14671208; 11120765; 11295725 to 11295725; 29241729; 30443250; 17635943; 18951619; 11120765; 16741580; 14671208
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FASLG Eleanor Williams Source Other was added to FASLG.
Publications for gene FASLG were updated from 17605793; 20301287; 8787672; 17605793; 27848183 to 8806292; 16537120; 16394653; 8787672; 20301287; 17605793; 26907631; 27848183; 25451160; 22857792; 7511063; 22983577
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FAS Eleanor Williams Source Other was added to FAS.
Publications for gene FAS were updated from 7540117; 9028321; 9821419; 9927496; 10709732; 15459302; 8929361; 28668589; 26258116 to 26258116; 10709732; 15459302; 28668589; 8806292; 16537120; 16394653; 7540117; 26907631; 9927496; 9028321; 8929361; 9821419; 25451160; 22857792; 7511063; 22983577
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 DOCK8 Eleanor Williams Source Other was added to DOCK8.
Publications for gene DOCK8 were updated from 19776401; 20004785; 25627830; 25724123 to 25724123; 20004785; 25627830; 19776401
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CTLA4 Eleanor Williams Source Other was added to CTLA4.
Publications for gene CTLA4 were updated from 25213377; 25329329 to 25213377; 25329329; 29729943
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 COPA Eleanor Williams Source Other was added to COPA.
Publications for gene COPA were updated from 25894502; 28956095; 25894502; 29137621 to 28956095; 25894502; 29137621
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CARD14 Eleanor Williams Source Other was added to CARD14.
Publications for gene CARD14 were updated from 23648549; 22521418; 22703878; 23067081; 29704870; 29689250; 23711932; 30248356; 29980436 to 22521418; 30248356; 23648549; 29689250; 22703878; 29980436; 23067081; 29704870; 23711932
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CARD11 Eleanor Williams Source Other was added to CARD11.
Publications for gene CARD11 were updated from 25352053; 23374270; 29074947; 23561803; 23129749; 30170123; 28628108; 28826773 to 29074947; 30170123; 28628108; 23129749; 25352053; 23374270; 23561803; 26289640; 28826773
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 BCL10 Eleanor Williams Source Other was added to BCL10.
Publications for gene BCL10 were updated from 32048120; 25365219; 32086639 to 32086639; 25365219; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 AIRE Eleanor Williams Source Other was added to AIRE.
Publications for gene AIRE were updated from 28911151; 29437776; 29108822; 9398839; 9837820; 9888391; 10677297; 11836330; 19758376; 11600535; 19807739 to 19758376; 29949487; 29108822; 28257655; 19807739; 10677297; 9398839; 11600535; 29483906; 9888391; 28911151; 9735375; 11836330; 29437776; 9837820; 30565240
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ADAM17 Eleanor Williams Source Other was added to ADAM17.
Publications for gene ADAM17 were updated from 22010916; 28930861; 20603312; 32048120; 25171914; 11149563; 25058236; 32086639; 29560122; 26683521; 25804906 to 29560122; 22010916; 25058236; 32048120; 20603312; 32086639; 26683521; 11149563; 25804906; 25171914; 28930861
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ADA2 Eleanor Williams Source Other was added to ADA2.
Publications for gene ADA2 were updated from 24552284; 24552285; 26922074; 29564582 to 24552284; 24552285; 29564582; 27059682; 26922074; 27444081
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ACP5 Eleanor Williams Source Other was added to ACP5.
Publications for gene ACP5 were updated from 26789720; 26951490; 26346816; 18924170; 21217755; 26789720; 21217752 to 21217755; 26789720; 21217752; 18924170; 26951490; 26346816
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TNFRSF4 Eleanor Williams Source Other was added to TNFRSF4.
Publications for gene TNFRSF4 were updated from 32048120; 32086639 to 32086639; 23897980; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SEMA3E Eleanor Williams Source Other was added to SEMA3E.
Publications for gene SEMA3E were updated from 12144540; 1735828; 32048120; 21055784; 32086639 to 12144540; 1735828; 11241468; 32048120; 21055784; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RNU4ATAC Eleanor Williams Source Other was added to RNU4ATAC.
Publications for gene RNU4ATAC were updated from 32048120; 32086639 to 26522830; 32086639; 21474760; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RELB Eleanor Williams Source Other was added to RELB.
Publications for gene RELB were updated from 32048120; 26385063; 32086639 to 26385063; 32086639; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NFAT5 Eleanor Williams Source Other was added to NFAT5.
Publications for gene NFAT5 were updated from 32048120; 32086639 to 32086639; 25667416; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 KMT2D Eleanor Williams Source Other was added to KMT2D.
Publications for gene KMT2D were updated from 25142838; 32048120; 15887282; 15523604; 26411453; 32086639 to 25142838; 15523604; 21671394; 32048120; 15887282; 21607748; 32086639; 23913813; 26411453
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 KDM6A Eleanor Williams Source Other was added to KDM6A.
Publications for gene KDM6A were updated from 25546742; 25142838; 32048120; 15887282; 15523604; 26411453; 32086639 to 25142838; 15523604; 32048120; 25546742; 15887282; 32086639; 26411453; 22197486; 23076834
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 JAK1 Eleanor Williams Source Other was added to JAK1.
Publications for gene JAK1 were updated from 32048120; 28111307; 32086639 to 32086639; 28111307; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FAAP24 Eleanor Williams Source Other was added to FAAP24.
Publications for gene FAAP24 were updated from 32048120; 27473539; 32086639 to 32086639; 17289582; 27473539; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 AP3D1 Eleanor Williams Source Other was added to AP3D1.
Publications for gene AP3D1 were updated from 32048120; 26744459; 32086639 to 32086639; 26744459; 30472485; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TAPBP Eleanor Williams Source Other was added to TAPBP.
Publications for gene TAPBP were updated from 32048120; 12149238; 32086639 to 32086639; 12149238; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RNF31 Eleanor Williams Source Other was added to RNF31.
Publications for gene RNF31 were updated from 32048120; 26008899; 32086639; 30936877 to 30936877; 32086639; 26008899; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RHOH Eleanor Williams Source Other was added to RHOH.
Publications for gene RHOH were updated from 32048120; 22850876; 24189071; 32086639 to 32086639; 24189071; 22850876; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD8A Eleanor Williams Source Other was added to CD8A.
Publications for gene CD8A were updated from 32048120; 17658607; 11435463; 32086639 to 32048120; 32086639; 26563160; 17658607; 11435463
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 BCL11B Eleanor Williams Source Other was added to BCL11B.
Publications for gene BCL11B were updated from 32048120; 27959755; 29296816; 32086639 to 27959755; 32086639; 29296816; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ZAP70 Eleanor Williams Publications for gene ZAP70 were updated from 8202713; 19548248; 18509675; 26783323; 25732729; 25805655 to 1333922; 8202713; 19548248; 21094993; 18509675; 26783323; 2511270; 25732729; 8124727; 25805655
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ZAP70 Eleanor Williams Source Other was added to ZAP70.
Publications for gene ZAP70 were updated from to 8202713; 19548248; 18509675; 26783323; 25732729; 25805655
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TTC7A Eleanor Williams Source Other was added to TTC7A.
Publications for gene TTC7A were updated from 24292712; 23423984; 23830146; 24417819; 24417819 to 23423984; 23830146; 24292712; 24417819
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TPP2 Eleanor Williams Source Other was added to TPP2.
Publications for gene TPP2 were updated from 25414442; 25525876 to 25414442; 25525876
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TCN2 Eleanor Williams Source Other was added to TCN2.
Publications for gene TCN2 were updated from 24305960; 7980584; 7849710; 20352340; 18956254 to 18956254; 20352340; 7849710; 7980584; 12107818; 19373259; 24305960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TAP2 Eleanor Williams Source Other was added to TAP2.
Publications for gene TAP2 were updated from 7517574; 10560675; 11529920; 20083708 to 11529920; 7517574; 10560675; 20083708
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 TAP1 Eleanor Williams Source Other was added to TAP1.
Publications for gene TAP1 were updated from to 11529920; 7517574; 10560675; 20083708; 10074494
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STIM1 Eleanor Williams Source Other was added to STIM1.
Publications for gene STIM1 were updated from 19420366; 20876309; 22190180; 24621671; 26560041 to 26560041; 20876309; 22190180; 19420366; 24621671; 24570283
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STAT5B Eleanor Williams Source Other was added to STAT5B.
Publications for gene STAT5B were updated from 13679528; 16920911; 15827093; 16787985; 17030597; 17389811; 20538865; 26703237; 29844444 to 29844444; 26703237; 17030597; 16920911; 15827093; 16787985; 17389811; 13679528; 20538865
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SP110 Eleanor Williams Source Other was added to SP110.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SMARCAL1 Eleanor Williams Source Other was added to SMARCAL1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 SLC46A1 Eleanor Williams Source Other was added to SLC46A1.
Publications for gene SLC46A1 were updated from 17129779; 17446347; 27664775 to 17129779; 27664775; 17446347
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RMRP Eleanor Williams Source Other was added to RMRP.
Publications for gene RMRP were updated from 25663137; 26830278; 26279652; 24217815; 3582365; 2328993 to 25663137; 3582365; 14569125; 12107819; 11207361; 26830278; 24217815; 26279652; 2328993
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RFXAP Eleanor Williams Source Other was added to RFXAP.
Publications for gene RFXAP were updated from 9118943; 9287230; 22390233; 20197681; 18336911; 12498778; 9806639 to 22390233; 9118943; 9806639; 9806639; 9287230; 18336911; 20197681; 12498778
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RFXANK Eleanor Williams Source Other was added to RFXANK.
Publications for gene RFXANK were updated from 11313409; 12618906; 22863278; 20414676; 9806546 to 20414676; 9806546; 12618906; 22863278; 11313409
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RFX5 Eleanor Williams Source Other was added to RFX5.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RBCK1 Eleanor Williams Source Other was added to RBCK1.
Publications for gene RBCK1 were updated from 23104095; 29260357 to 23798481; 610924; 29260357; 23104095
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RASGRP1 Eleanor Williams Source Other was added to RASGRP1.
Publications for gene RASGRP1 were updated from 30030704; 29282224; 29155103; 28822832; 27776107 to 29155103; 28822832; 29282224; 27776107; 30030704
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RAG2 Eleanor Williams Source Other was added to RAG2.
Publications for gene RAG2 were updated from to 16960852; 30046960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RAG1 Eleanor Williams Source Other was added to RAG1.
Publications for gene RAG1 were updated from to 16960852; 8810255; 30046960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RAB27A Eleanor Williams Source Other was added to RAB27A.
Publications for gene RAB27A were updated from 12058346; 12531900; 12522785; 15163896; 15163896 to 12531900; 9486701; 12058346; 10835631; 24134793; 12522785; 15163896; 16517541
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PTPRC Eleanor Williams Source Other was added to PTPRC.
Publications for gene PTPRC were updated from 10700239; 11145714; 22689986 to 11145714; 10700239; 22689986
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PSMB8 Eleanor Williams Source Other was added to PSMB8.
Publications for gene PSMB8 were updated from 21129723; 21953331; 21881205; 21852578; 21953331 to 21881205; 20159315; 21953331; 21129723; 20534754; 21852578
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PRKCD Eleanor Williams Publications for gene PRKCD were updated from 23319571; 27541826; 23666743; 23430113 to 19075392; 23430113; 25842288; 23722905; 23319571; 27541826; 23666743
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PRKCD Eleanor Williams Source Other was added to PRKCD.
Publications for gene PRKCD were updated from 23319571; 23666743; 23430113 to 23319571; 27541826; 23666743; 23430113
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PNP Eleanor Williams Source Other was added to PNP.
Publications for gene PNP were updated from to 1384322; 3029074
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 PEPD Eleanor Williams Source Other was added to PEPD.
Publications for gene PEPD were updated from 2365824; 1972707; 6637477; 2365824; 16470701; 8900231; 15309682; 17142620; 19308961 to 8900231; 2365824; 17142620; 26110198; 15309682; 6637477; 16470701; 19308961; 22726576; 1972707
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ORAI1 Eleanor Williams Source Other was added to ORAI1.
Publications for gene ORAI1 were updated from 16582901; 20004786 to 7798233; 16582901; 8814256; 20004786
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NHEJ1 Eleanor Williams Source Other was added to NHEJ1.
Publications for gene NHEJ1 were updated from to 16439204; 20113890
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 NFKBIA Eleanor Williams Source Other was added to NFKBIA.
Publications for gene NFKBIA were updated from 14523047; 15337789; 17931563; 18412279 to 15337789; 23708964; 18412279; 17931563; 28597146; 28417298; 14523047
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MYSM1 Eleanor Williams Source Other was added to MYSM1.
Publications for gene MYSM1 were updated from 24288411; 26220525; 28115216; 28446309; 22184403; 26474655 to 26474655; 26220525; 24288411; 28446309; 28115216; 22184403
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MTHFD1 Eleanor Williams Source Other was added to MTHFD1.
Publications for gene MTHFD1 were updated from 27707659; 25633902 to 27707659; 25633902; 21813566; 9611072; 12384833
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 MAP3K14 Eleanor Williams Source Other was added to MAP3K14.
Publications for gene MAP3K14 were updated from 29230214; 25406581; 29259025 to 29230214; 25406581; 29259025
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LIG4 Eleanor Williams Source Other was added to LIG4.
Publications for gene LIG4 were updated from to 20113890; 16357942
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LAT Eleanor Williams Source Other was added to LAT.
Publications for gene LAT were updated from 27522155; 27242165 to 27522155; 27242165
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 JAK3 Eleanor Williams Source Other was added to JAK3.
Publications for gene JAK3 were updated from to 7481768; 7659163
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ITK Eleanor Williams Source Other was added to ITK.
Publications for gene ITK were updated from 19425169; 22289921; 21109689 to 29867957; 22289921; 21109689; 19425169
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ITCH Eleanor Williams Source Other was added to ITCH.
Publications for gene ITCH were updated from 20170897; 26854353; 19592251; 20962770; 27322655 to 30705142; 20962770; 26854353; 20170897; 19592251; 27322655
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL7R Eleanor Williams Source Other was added to IL7R.
Publications for gene IL7R were updated from to 9843216
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL2RG Eleanor Williams Source Other was added to IL2RG.
Publications for gene IL2RG were updated from to 8712778; 9921912; 8462096; 7668284
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IL10 Eleanor Williams Source Other was added to IL10.
Publications for gene IL10 were updated from 19890111; 20951137 to 19890111; 20951137; 22236434
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IKBKG Eleanor Williams Source Other was added to IKBKG.
Publications for gene IKBKG were updated from 11047757 to 16818673; 11179023; 16950813; 15356572; 11047757
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 IKBKB Eleanor Williams Source Other was added to IKBKB.
Publications for gene IKBKB were updated from 25216719; 24369075; 30337470 to 30337470; 25216719; 24369075
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ICOS Eleanor Williams Source Other was added to ICOS.
Publications for gene ICOS were updated from 29867948; 28861081; 12577056; 15507387; 19380800; 25678089; 26399252; 10413651; 29867948; 25678089; 24795713; 29226302; 29226301 to 10413651; 26399252; 25678089; 29226301; 19380800; 28861081; 15507387; 24795713; 12577056; 29226302; 29867948
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FOXN1 Eleanor Williams Source Other was added to FOXN1.
Publications for gene FOXN1 were updated from 28636882; 15180707; 21507891; 11159512; 31447097; 10206641; 28077132; 29593714 to 11159512; 29593714; 21507891; 10206641; 28636882; 15180707; 28077132; 31447097
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FAT4 Eleanor Williams Source Other was added to FAT4.
Publications for gene FAT4 were updated from 24913602; 25616299; 29681106 to 29681106; 22473091; 22469822; 25616299; 24056717; 24913602
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FADD Eleanor Williams Source Other was added to FADD.
Publications for gene FADD were updated from 21109225; 17656375; 25794656 to 18070632; 17656375; 25794656; 21109225
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 EXTL3 Eleanor Williams Source Other was added to EXTL3.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 EPG5 Eleanor Williams Source Other was added to EPG5.
Publications for gene EPG5 were updated from 23222957; 25331754; 26917586; 26395118; 23838600; 23674064; 28624465 to 23674064; 28624465; 26917586; 28168853; 26395118; 23222957; 23838600; 25331754
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 DOCK2 Eleanor Williams Source Other was added to DOCK2.
Publications for gene DOCK2 were updated from 26083206; 28694805; 29503648 to 26083206; 29503648; 29204803; 28694805
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 DCLRE1C Eleanor Williams Source Other was added to DCLRE1C.
Publications for gene DCLRE1C were updated from to 32092471; 11336668; 12569164; 10416610; 26476407; 24144642; 31393046; 12406895; 12055248; 16540517; 15731174
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CTPS1 Eleanor Williams Source Other was added to CTPS1.
Publications for gene CTPS1 were updated from 24870241; 26424649; 27638562; 17576681; 9536098 to 26424649; 17576681; 27638562; 9536098; 29884857; 24870241
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CORO1A Eleanor Williams Source Other was added to CORO1A.
Publications for gene CORO1A were updated from 23522482; 18836449; 19097825 to 23522482; 19097825; 18836449; 25073507
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CIITA Eleanor Williams Source Other was added to CIITA.
Publications for gene CIITA were updated from 8402893; 9099848; 11862382 to 8402893; 11862382; 9099848
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD70 Eleanor Williams Source Other was added to CD70.
Publications for gene CD70 were updated from 28011863; 28011864; 29434583 to 28011864; 28011863; 29434583
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD40LG Eleanor Williams Source Other was added to CD40LG.
Publications for gene CD40LG were updated from 7679801; 7678782; 7679206; 8094231; 7586644; 17146684; 7882172; 11875495; 20301576 to 11875495; 7678782; 7679801; 27189378; 8094231; 20301576; 27697500; 19931163; 17146684; 7882172; 25840720; 7586644; 7679206
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD40 Eleanor Williams Source Other was added to CD40.
Publications for gene CD40 were updated from 11675497; 12584544; 20301287; 17502893 to 11675497; 20301287; 12584544; 24122029; 17502893
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD3G Eleanor Williams Source Other was added to CD3G.
Publications for gene CD3G were updated from 1635567; 17277165 to 29653965; 17277165; 1635567; 24910257
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD3E Eleanor Williams Source Other was added to CD3E.
Publications for gene CD3E were updated from to 15546002; 8490660
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD3D Eleanor Williams Source Other was added to CD3D.
Publications for gene CD3D were updated from to 14602880; 21926461; 15546002
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD27 Eleanor Williams Source Other was added to CD27.
Publications for gene CD27 were updated from 22197273; 22801960; 25843314 to 25843314; 22801960; 22197273
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CD247 Eleanor Williams Source Other was added to CD247.
Publications for gene CD247 were updated from 16672702; 26690594; 17170122; 27555457; 25688246; https://doi.org/10.14785/lpsn-2014-0012; 26542031 to 26690594; 26542031; 17170122; 27555457; 25688246; 16672702; https://doi.org/10.14785/lpsn-2014-0012
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CCBE1 Eleanor Williams Source Other was added to CCBE1.
Publications for gene CCBE1 were updated from 19935664; 19911200; 24913602 to 19911200; 24913602; 19935664
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CASP8 Eleanor Williams Source Other was added to CASP8.
Publications for gene CASP8 were updated from 12353035; 16157684; 24240292; 20301287 to 12353035; 20301287; 16157684; 24240292; 15492869
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CASP10 Eleanor Williams Source Other was added to CASP10.
Publications for gene CASP10 were updated from 25663566; 21447005; 10412980; 16446975; 9028957; 16611303 to 25663566; 16446975; 16611303; 10412980; 21447005; 27378136; 9028957
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 CARMIL2 Eleanor Williams Source Other was added to CARMIL2.
Publications for gene CARMIL2 were updated from 27896283; 27647349; 28112205 to 27647349; 27896283; 28112205; 29479355
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 BACH2 Eleanor Williams Source Other was added to BACH2.
Publications for gene BACH2 were updated from 27807919; 27680876; 28530713 to 27680876; 28530713; 27807919; 30527062
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 B2M Eleanor Williams Source Other was added to B2M.
Publications for gene B2M were updated from 4186801; 25702838 to 25702838; 4186801
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 AP3B1 Eleanor Williams Source Other was added to AP3B1.
Publications for gene AP3B1 were updated from 10024875; 14566336; 8042664; 11809908; 16537806; 19679886; 23403622; 16507770; 28585318 to 19679886; 11809908; 10024875; 16551969; 16537806; 16507770; 28585318; 30974211; 23403622; 8042664; 14566336
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 AK2 Eleanor Williams Source Other was added to AK2.
Publications for gene AK2 were updated from 19043416; 19043417 to 19043416; 19043417
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 ADA Eleanor Williams Source Other was added to ADA.
Publications for gene ADA were updated from to 3475710; 6134754; 8227344; 2567118; 6200875; 2166947
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ZAP70 Eleanor Williams edited their review of gene: ZAP70: Added comment: The following PubMed IDs were added to gene ZAP70 (OMIM gene MIM#176947): 19548248;18509675;8202713;26783323;25805655;25732729. These publications have been associated with the gene by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 19548248, 18509675, 8202713, 26783323, 25805655, 25732729
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 XIAP Eleanor Williams edited their review of gene: XIAP: Added comment: The following PubMed IDs were added to entity XIAP: 31754776;23973892;21119115;26581487;23131490. These publications have been associated with OMIM phenotype MIM#300635, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 31754776, 23973892, 21119115, 26581487, 23131490
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 UNC13D Eleanor Williams reviewed gene: UNC13D: Rating: ; Mode of pathogenicity: ; Publications: 27914778, 14622600, 17993578, 29312353; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TTC7A Eleanor Williams reviewed gene: TTC7A: Rating: ; Mode of pathogenicity: ; Publications: 24292712, 23423984, 23830146; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TREX1 Eleanor Williams reviewed gene: TREX1: Rating: ; Mode of pathogenicity: ; Publications: 25604658, 17846997; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TRAC Eleanor Williams reviewed gene: TRAC: Rating: ; Mode of pathogenicity: ; Publications: 21206088, 3464003; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TPP2 Eleanor Williams reviewed gene: TPP2: Rating: ; Mode of pathogenicity: ; Publications: 25414442; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TNFRSF4 Eleanor Williams reviewed gene: TNFRSF4: Rating: ; Mode of pathogenicity: ; Publications: 23897980; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TNFRSF1A Eleanor Williams reviewed gene: TNFRSF1A: Rating: ; Mode of pathogenicity: ; Publications: 11115159, 23965844, 12209523; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TNFAIP3 Eleanor Williams reviewed gene: TNFAIP3: Rating: ; Mode of pathogenicity: ; Publications: 27845235, 31164164; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TMEM173 Eleanor Williams edited their review of gene: TMEM173: Added comment: The following PubMed IDs were added to entity TMEM173: 25029335;25401470. These publications have been associated with OMIM phenotype MIM#615934, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 25029335, 25401470
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TFRC Eleanor Williams reviewed gene: TFRC: Rating: ; Mode of pathogenicity: ; Publications: 26642240; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TCN2 Eleanor Williams reviewed gene: TCN2: Rating: ; Mode of pathogenicity: ; Publications: 7849710, 19373259, 12107818; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TBX1 Eleanor Williams edited their review of gene: TBX1: Added comment: The following PubMed IDs were added to entity TBX1: 12548732. These publications have been associated with OMIM phenotype MIM#188400, which is listed for this entity, by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 12548732
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TAPBP Eleanor Williams commented on gene: TAPBP: The following PubMed IDs were added to gene TAPBP (OMIM gene MIM#601962): 12149238. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TAP2 Eleanor Williams edited their review of gene: TAP2: Added comment: The following PubMed IDs were added to gene TAP2 (OMIM gene MIM#170261): 20083708;7517574;10560675;11529920. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 20083708, 7517574, 10560675, 11529920
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 TAP1 Eleanor Williams edited their review of gene: TAP1: Added comment: The following PubMed IDs were added to gene TAP1 (OMIM gene MIM#170260): 20083708;7517574;10560675;10074494;11529920. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 20083708, 7517574, 10560675, 10074494, 11529920
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STXBP2 Eleanor Williams reviewed gene: STXBP2: Rating: ; Mode of pathogenicity: ; Publications: 19804848, 30557712, 22451424, 19884660, 29776323; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STX11 Eleanor Williams reviewed gene: STX11: Rating: ; Mode of pathogenicity: ; Publications: 16582076, 18710388, 15703195; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STK4 Eleanor Williams reviewed gene: STK4: Rating: ; Mode of pathogenicity: ; Publications: 22174160, 26801501, 26117625, 22294732; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STIM1 Eleanor Williams edited their review of gene: STIM1: Added comment: The following PubMed IDs were added to gene STIM1 (OMIM gene MIM#605921): 24570283;22190180;20876309;19420366. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 24570283, 22190180, 20876309, 19420366
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STAT5B Eleanor Williams edited their review of gene: STAT5B: Added comment: The following PubMed IDs were added to gene STAT5B (OMIM gene MIM#604260): 13679528;16920911. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 13679528, 16920911
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STAT3 Eleanor Williams edited their review of gene: STAT3: Added comment: The following PubMed IDs were added to entity STAT3: 25349174;28402852;25359994;25038750. These publications have been associated with OMIM phenotype MIM#615952, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 25349174, 28402852, 25359994, 25038750
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SP110 Eleanor Williams edited their review of gene: SP110: Added comment: The following PubMed IDs were added to gene SP110 (OMIM gene MIM#604457): 16648851. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 16648851
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SMARCAL1 Eleanor Williams edited their review of gene: SMARCAL1: Added comment: The following PubMed IDs were added to gene SMARCAL1 (OMIM gene MIM#606622): 17089404;11799392. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 17089404, 11799392
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SLC46A1 Eleanor Williams edited their review of gene: SLC46A1: Added comment: The following PubMed IDs were added to gene SLC46A1 (OMIM gene MIM#611672): 17446347;17129779. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 17446347, 17129779
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SLC29A3 Eleanor Williams edited their review of gene: SLC29A3: Added comment: The following PubMed IDs were added to entity SLC29A3: 20619369;20140240. These publications have been associated with OMIM phenotype MIM#602782, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 20619369, 20140240
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SH3BP2 Eleanor Williams reviewed gene: SH3BP2: Rating: ; Mode of pathogenicity: ; Publications: 11113824, 16053841; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SH2D1A Eleanor Williams edited their review of gene: SH2D1A: Added comment: The following PubMed IDs were added to entity SH2D1A: 31754776;21119115;25085526. These publications have been associated with OMIM phenotype MIM#308240, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 31754776, 21119115, 25085526
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SEMA3E Eleanor Williams edited their review of gene: SEMA3E: Added comment: The following PubMed IDs were added to gene SEMA3E (OMIM gene MIM#608166): 11241468. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 11241468
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RNU4ATAC Eleanor Williams reviewed gene: RNU4ATAC: Rating: ; Mode of pathogenicity: ; Publications: 21474760, 26522830; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RNF31 Eleanor Williams reviewed gene: RNF31: Rating: ; Mode of pathogenicity: ; Publications: 26008899; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RMRP Eleanor Williams reviewed gene: RMRP: Rating: ; Mode of pathogenicity: ; Publications: 14569125, 11207361, 12107819; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RHOH Eleanor Williams reviewed gene: RHOH: Rating: ; Mode of pathogenicity: ; Publications: 22850876, 24189071; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RFXAP Eleanor Williams reviewed gene: RFXAP: Rating: ; Mode of pathogenicity: ; Publications: 20197681, 9287230, 9806639, 18336911, 12498778, 22390233, 9118943; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RFXANK Eleanor Williams reviewed gene: RFXANK: Rating: ; Mode of pathogenicity: ; Publications: 11313409, 12618906, 9806546, 20414676, 22863278; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RFX5 Eleanor Williams reviewed gene: RFX5: Rating: ; Mode of pathogenicity: ; Publications: 7744245, 9401005; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RELB Eleanor Williams reviewed gene: RELB: Rating: ; Mode of pathogenicity: ; Publications: 26385063; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RBCK1 Eleanor Williams reviewed gene: RBCK1: Rating: ; Mode of pathogenicity: ; Publications: 23798481, 610924; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RASGRP1 Eleanor Williams reviewed gene: RASGRP1: Rating: ; Mode of pathogenicity: ; Publications: 29155103, 30030704, 27776107; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RAG2 Eleanor Williams reviewed gene: RAG2: Rating: ; Mode of pathogenicity: ; Publications: 30046960, 16960852; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RAG1 Eleanor Williams reviewed gene: RAG1: Rating: ; Mode of pathogenicity: ; Publications: 30046960, 16960852, 8810255; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RAB27A Eleanor Williams reviewed gene: RAB27A: Rating: ; Mode of pathogenicity: ; Publications: 24134793, 10835631, 16517541, 9486701; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PTPRC Eleanor Williams reviewed gene: PTPRC: Rating: ; Mode of pathogenicity: ; Publications: 22689986, 11145714, 10700239; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PSTPIP1 Eleanor Williams reviewed gene: PSTPIP1: Rating: ; Mode of pathogenicity: ; Publications: 9212761, 22161697, 21532836; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PSMB8 Eleanor Williams reviewed gene: PSMB8: Rating: ; Mode of pathogenicity: ; Publications: 20159315, 20534754; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PRKCD Eleanor Williams edited their review of gene: PRKCD: Added comment: The following PubMed IDs were added to gene PRKCD (OMIM gene MIM#176977): 27541826;23666743;23319571. These publications have been associated with the gene by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 27541826, 23666743, 23319571
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PRF1 Eleanor Williams reviewed gene: PRF1: Rating: ; Mode of pathogenicity: ; Publications: 10583959, 22248322, 28468610, 28806468; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 POLA1 Eleanor Williams edited their review of gene: POLA1: Added comment: The following PubMed IDs were added to entity POLA1: 15804299;6794369. These publications have been associated with OMIM phenotype MIM#301220, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 15804299, 6794369
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PNP Eleanor Williams reviewed gene: PNP: Rating: ; Mode of pathogenicity: ; Publications: 3029074, 1384322; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PLCG2 Eleanor Williams reviewed gene: PLCG2: Rating: ; Mode of pathogenicity: ; Publications: 23000145, 22236196, 25760457; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PEPD Eleanor Williams reviewed gene: PEPD: Rating: ; Mode of pathogenicity: ; Publications: 26110198, 22726576; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 OTULIN Eleanor Williams reviewed gene: OTULIN: Rating: ; Mode of pathogenicity: ; Publications: 27559085; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ORAI1 Eleanor Williams reviewed gene: ORAI1: Rating: ; Mode of pathogenicity: ; Publications: 8814256, 7798233, 16582901; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NOD2 Eleanor Williams reviewed gene: NOD2: Rating: ; Mode of pathogenicity: ; Publications: 25416713, 28887115, 19479837, 25136265; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NLRP3 Eleanor Williams edited their review of gene: NLRP3: Added comment: The following PubMed IDs were added to entity NLRP3: 12032915. These publications have been associated with OMIM phenotype MIM#607115, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 12032915
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NLRP12 Eleanor Williams reviewed gene: NLRP12: Rating: ; Mode of pathogenicity: ; Publications: 18230725, 27633793, 21360512; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NLRP1 Eleanor Williams reviewed gene: NLRP1: Rating: ; Mode of pathogenicity: ; Publications: 27965258; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NLRC4 Eleanor Williams edited their review of gene: NLRC4: Added comment: The following PubMed IDs were added to entity NLRC4: 25385754. These publications have been associated with OMIM phenotype MIM#616115, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 25385754
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NHEJ1 Eleanor Williams reviewed gene: NHEJ1: Rating: ; Mode of pathogenicity: ; Publications: 20113890, 16439204; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NFKBIA Eleanor Williams reviewed gene: NFKBIA: Rating: ; Mode of pathogenicity: ; Publications: 23708964, 28597146, 14523047, 28417298; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 NFAT5 Eleanor Williams reviewed gene: NFAT5: Rating: ; Mode of pathogenicity: ; Publications: 25667416; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MYSM1 Eleanor Williams reviewed gene: MYSM1: Rating: ; Mode of pathogenicity: ; Publications: 24288411, 28115216, 22184403; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MVK Eleanor Williams reviewed gene: MVK: Rating: ; Mode of pathogenicity: ; Publications: 22038276, 21708801, 19011501; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MTHFD1 Eleanor Williams reviewed gene: MTHFD1: Rating: ; Mode of pathogenicity: ; Publications: 21813566, 9611072, 12384833; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MSN Eleanor Williams reviewed gene: MSN: Rating: ; Mode of pathogenicity: ; Publications: 27405666, 29556235; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MEFV Eleanor Williams commented on gene: MEFV: The following PubMed IDs were added to entity MEFV: 9266193;15643295. These publications have been associated with OMIM phenotype MIM#134610, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MAP3K14 Eleanor Williams reviewed gene: MAP3K14: Rating: ; Mode of pathogenicity: ; Publications: 29230214, 29259025, 25406581; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MALT1 Eleanor Williams reviewed gene: MALT1: Rating: ; Mode of pathogenicity: ; Publications: 24332264, 25627829, 23727036; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 MAGT1 Eleanor Williams reviewed gene: MAGT1: Rating: ; Mode of pathogenicity: ; Publications: 21796205, 29635109; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LYST Eleanor Williams reviewed gene: LYST: Rating: ; Mode of pathogenicity: ; Publications: 26944273, 18043242, 29939658, 8717042; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LRBA Eleanor Williams reviewed gene: LRBA: Rating: ; Mode of pathogenicity: ; Publications: 25931386, 26707784, 22608502, 26768763; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LPIN2 Eleanor Williams reviewed gene: LPIN2: Rating: ; Mode of pathogenicity: ; Publications: 27252506, 2809904, 10969284; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LIG4 Eleanor Williams reviewed gene: LIG4: Rating: ; Mode of pathogenicity: ; Publications: 16357942, 20113890; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LCK Eleanor Williams reviewed gene: LCK: Rating: ; Mode of pathogenicity: ; Publications: 22985903, 11351273, 9664084; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LAT Eleanor Williams reviewed gene: LAT: Rating: ; Mode of pathogenicity: ; Publications: 27522155; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 KMT2D Eleanor Williams reviewed gene: KMT2D: Rating: ; Mode of pathogenicity: ; Publications: 23913813, 21671394, 21607748; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 KDM6A Eleanor Williams reviewed gene: KDM6A: Rating: ; Mode of pathogenicity: ; Publications: 23076834, 22197486; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 JAK3 Eleanor Williams reviewed gene: JAK3: Rating: ; Mode of pathogenicity: ; Publications: 7659163, 7481768; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 JAK1 Eleanor Williams reviewed gene: JAK1: Rating: ; Mode of pathogenicity: ; Publications: 28111307; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ITK Eleanor Williams reviewed gene: ITK: Rating: ; Mode of pathogenicity: ; Publications: 29867957; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ITCH Eleanor Williams reviewed gene: ITCH: Rating: ; Mode of pathogenicity: ; Publications: 30705142, 20170897; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL7R Eleanor Williams reviewed gene: IL7R: Rating: ; Mode of pathogenicity: ; Publications: 9843216; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL36RN Eleanor Williams reviewed gene: IL36RN: Rating: ; Mode of pathogenicity: ; Publications: 21848462, 21839423; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL2RG Eleanor Williams reviewed gene: IL2RG: Rating: ; Mode of pathogenicity: ; Publications: 8462096, 9921912, 8712778, 7668284; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL2RA Eleanor Williams reviewed gene: IL2RA: Rating: ; Mode of pathogenicity: ; Publications: 17196245, 23416241, 24116927; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL21R Eleanor Williams reviewed gene: IL21R: Rating: ; Mode of pathogenicity: ; Publications: 23440042, 12700598; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL21 Eleanor Williams reviewed gene: IL21: Rating: ; Mode of pathogenicity: ; Publications: 24746753; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL1RN Eleanor Williams reviewed gene: IL1RN: Rating: ; Mode of pathogenicity: ; Publications: 22127713, 19494218, 19494219; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL10RB Eleanor Williams reviewed gene: IL10RB: Rating: ; Mode of pathogenicity: ; Publications: 22236434; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL10RA Eleanor Williams reviewed gene: IL10RA: Rating: ; Mode of pathogenicity: ; Publications: 22236434; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IL10 Eleanor Williams reviewed gene: IL10: Rating: ; Mode of pathogenicity: ; Publications: 22236434; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IKBKG Eleanor Williams reviewed gene: IKBKG: Rating: ; Mode of pathogenicity: ; Publications: 16818673, 16950813, 11047757, 15356572, 11179023; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 IKBKB Eleanor Williams reviewed gene: IKBKB: Rating: ; Mode of pathogenicity: ; Publications: 24369075, 25216719; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ICOS Eleanor Williams reviewed gene: ICOS: Rating: ; Mode of pathogenicity: ; Publications: 12577056, 28861081; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FOXP3 Eleanor Williams reviewed gene: FOXP3: Rating: ; Mode of pathogenicity: ; Publications: 29241729, 18951619, 30443250; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FOXN1 Eleanor Williams reviewed gene: FOXN1: Rating: ; Mode of pathogenicity: ; Publications: 10206641; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FAT4 Eleanor Williams reviewed gene: FAT4: Rating: ; Mode of pathogenicity: ; Publications: 24056717, 22469822, 22473091, 24913602; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FASLG Eleanor Williams reviewed gene: FASLG: Rating: ; Mode of pathogenicity: ; Publications: 25451160, 7511063, 16537120, 22857792, 8806292, 22983577, 16394653, 26907631; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FAS Eleanor Williams reviewed gene: FAS: Rating: ; Mode of pathogenicity: ; Publications: 25451160, 7511063, 16537120, 22857792, 8806292, 22983577, 16394653, 26907631; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FADD Eleanor Williams reviewed gene: FADD: Rating: ; Mode of pathogenicity: ; Publications: 18070632, 25794656, 21109225; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FAAP24 Eleanor Williams reviewed gene: FAAP24: Rating: ; Mode of pathogenicity: ; Publications: 17289582, 27473539; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 EXTL3 Eleanor Williams reviewed gene: EXTL3: Rating: ; Mode of pathogenicity: ; Publications: 28148688, 28132690; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 EPG5 Eleanor Williams reviewed gene: EPG5: Rating: ; Mode of pathogenicity: ; Publications: 25331754, 28168853, 23222957; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 DOCK8 Eleanor Williams reviewed gene: DOCK8: Rating: ; Mode of pathogenicity: ; Publications: 25724123, 25627830, 19776401, 20004785; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 DOCK2 Eleanor Williams reviewed gene: DOCK2: Rating: ; Mode of pathogenicity: ; Publications: 29204803, 26083206; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 DCLRE1C Eleanor Williams reviewed gene: DCLRE1C: Rating: ; Mode of pathogenicity: ; Publications: 10416610, 32092471, 31393046, 26476407, 12055248, 12569164, 12406895, 11336668, 15731174, 24144642, 16540517; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CTPS1 Eleanor Williams reviewed gene: CTPS1: Rating: ; Mode of pathogenicity: ; Publications: 24870241, 29884857; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CTLA4 Eleanor Williams reviewed gene: CTLA4: Rating: ; Mode of pathogenicity: ; Publications: 29729943, 25213377, 25329329; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CORO1A Eleanor Williams reviewed gene: CORO1A: Rating: ; Mode of pathogenicity: ; Publications: 23522482, 19097825, 25073507; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 COPA Eleanor Williams reviewed gene: COPA: Rating: ; Mode of pathogenicity: ; Publications: 25894502; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CIITA Eleanor Williams reviewed gene: CIITA: Rating: ; Mode of pathogenicity: ; Publications: 11862382, 8402893, 9099848; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD8A Eleanor Williams reviewed gene: CD8A: Rating: ; Mode of pathogenicity: ; Publications: 17658607, 26563160, 11435463; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD70 Eleanor Williams reviewed gene: CD70: Rating: ; Mode of pathogenicity: ; Publications: 28011864, 28011863, 29434583; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD40LG Eleanor Williams reviewed gene: CD40LG: Rating: ; Mode of pathogenicity: ; Publications: 27189378, 19931163, 25840720, 27697500; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD40 Eleanor Williams reviewed gene: CD40: Rating: ; Mode of pathogenicity: ; Publications: 12584544, 24122029; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD3G Eleanor Williams reviewed gene: CD3G: Rating: ; Mode of pathogenicity: ; Publications: 29653965, 17277165, 24910257; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD3E Eleanor Williams reviewed gene: CD3E: Rating: ; Mode of pathogenicity: ; Publications: 15546002, 8490660; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD3D Eleanor Williams reviewed gene: CD3D: Rating: ; Mode of pathogenicity: ; Publications: 14602880, 15546002, 21926461; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD27 Eleanor Williams reviewed gene: CD27: Rating: ; Mode of pathogenicity: ; Publications: 25843314, 22801960; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CD247 Eleanor Williams reviewed gene: CD247: Rating: ; Mode of pathogenicity: ; Publications: 17170122; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CCBE1 Eleanor Williams reviewed gene: CCBE1: Rating: ; Mode of pathogenicity: ; Publications: 19911200, 19935664; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CASP8 Eleanor Williams reviewed gene: CASP8: Rating: ; Mode of pathogenicity: ; Publications: 12353035, 15492869; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CASP10 Eleanor Williams reviewed gene: CASP10: Rating: ; Mode of pathogenicity: ; Publications: 16446975, 27378136; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CARMIL2 Eleanor Williams reviewed gene: CARMIL2: Rating: ; Mode of pathogenicity: ; Publications: 27647349, 28112205, 29479355; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CARD14 Eleanor Williams reviewed gene: CARD14: Rating: ; Mode of pathogenicity: ; Publications: 22521418; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 CARD11 Eleanor Williams reviewed gene: CARD11: Rating: ; Mode of pathogenicity: ; Publications: 23561803, 23374270, 26289640; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 BCL11B Eleanor Williams commented on gene: BCL11B: The following PubMed IDs were added to gene BCL11B (OMIM gene MIM#606558): 27959755. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 BCL10 Eleanor Williams reviewed gene: BCL10: Rating: ; Mode of pathogenicity: ; Publications: 25365219; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 BACH2 Eleanor Williams reviewed gene: BACH2: Rating: ; Mode of pathogenicity: ; Publications: 28530713, 30527062; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 B2M Eleanor Williams reviewed gene: B2M: Rating: ; Mode of pathogenicity: ; Publications: 4186801, 25702838; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 AP3D1 Eleanor Williams reviewed gene: AP3D1: Rating: ; Mode of pathogenicity: ; Publications: 30472485, 26744459; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 AP3B1 Eleanor Williams reviewed gene: AP3B1: Rating: ; Mode of pathogenicity: ; Publications: 10024875, 16551969, 30974211; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 AP1S3 Eleanor Williams reviewed gene: AP1S3: Rating: ; Mode of pathogenicity: ; Publications: 24791904; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 AK2 Eleanor Williams reviewed gene: AK2: Rating: ; Mode of pathogenicity: ; Publications: 19043417; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 AIRE Eleanor Williams reviewed gene: AIRE: Rating: ; Mode of pathogenicity: ; Publications: 29483906, 9735375, 28257655, 30565240, 29949487; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ADAM17 Eleanor Williams edited their review of gene: ADAM17: Added comment: The following PubMed IDs were added to entity ADAM17: 22010916. These publications have been associated with OMIM phenotype MIM#614328, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 22010916
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ADA2 Eleanor Williams reviewed gene: ADA2: Rating: ; Mode of pathogenicity: ; Publications: 24552285, 24552284, 27059682, 27444081; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ADA Eleanor Williams reviewed gene: ADA: Rating: ; Mode of pathogenicity: ; Publications: 6200875, 8227344, 3475710, 2166947, 2567118, 6134754; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ACP5 Eleanor Williams reviewed gene: ACP5: Rating: ; Mode of pathogenicity: ; Publications: 26951490; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.207 ZAP70 Eleanor Williams reviewed gene: ZAP70: Rating: ; Mode of pathogenicity: ; Publications: 18509675, 26783323, 1333922, 21094993, 8124727, 2511270; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.207 PRKCD Eleanor Williams reviewed gene: PRKCD: Rating: ; Mode of pathogenicity: ; Publications: 23722905, 25842288, 19075392; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.207 NLRP3 Eleanor Williams edited their review of gene: NLRP3: Added comment: The following PubMed IDs were added to entity NLRP3: 14476827;14872505;11590390. These publications have been associated with OMIM phenotype MIM#191900, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 14476827, 14872505, 11590390
Primary immunodeficiency or monogenic inflammatory bowel disease v2.207 NLRC4 Eleanor Williams reviewed gene: NLRC4: Rating: ; Mode of pathogenicity: ; Publications: 25217960, 25217959; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.207 MEFV Eleanor Williams reviewed gene: MEFV: Rating: ; Mode of pathogenicity: ; Publications: 9266193, 15643295; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.207 BCL11B Eleanor Williams edited their review of gene: BCL11B: Added comment: The following PubMed IDs were added to entity BCL11B: 27959755. These publications have been associated with OMIM phenotype MIM#617237, which is listed for this entity, by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 27959755
Primary immunodeficiency or monogenic inflammatory bowel disease v2.206 NLRP3 Eleanor Williams reviewed gene: NLRP3: Rating: ; Mode of pathogenicity: ; Publications: 18423104, 11590390; Phenotypes: ; Mode of inheritance:
Intellectual disability v3.432 BCORL1 Arina Puzriakova Phenotypes for gene: BCORL1 were changed from Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality to Shukla-Vernon syndrome, 301029
Intellectual disability v3.431 BCORL1 Arina Puzriakova Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204; 30941876
Intellectual disability v3.430 BCORL1 Arina Puzriakova Classified gene: BCORL1 as Amber List (moderate evidence)
Intellectual disability v3.430 BCORL1 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber in line with the previous review by Rebecca Foulger. Severe ID only exhibited by 2/4 families. No additional papers recently published.
Intellectual disability v3.430 BCORL1 Arina Puzriakova Gene: bcorl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.429 MPV17 Ivone Leong Classified gene: MPV17 as Amber List (moderate evidence)
Intellectual disability v3.429 MPV17 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. While there are enough cases to support a gene-disease association, ID is part of a broader phenotype for this disorder. Affected individuals will more likely be assessed under mitchondrial panels. This gene is green in Mitochondrial liver disease, inborn errors of metabolism, possible mitochondrial disorder - nuclear genes and mitochondrial disorders panels.
Intellectual disability v3.429 MPV17 Ivone Leong Gene: mpv17 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.428 MPV17 Ivone Leong Phenotypes for gene: MPV17 were changed from Gene2Phenotype confirmed gene with ID HPO to Gene2Phenotype confirmed gene with ID HPO; Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), 256810
Retinal disorders v2.20 PRDM13 Zornitza Stark reviewed gene: PRDM13: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29258872, 28973654, 26507665, 30710461; Phenotypes: Macular dystrophy, North Carolina type MIM#136550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 POMGNT1 Zornitza Stark reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27391550, 26908613; Phenotypes: Retinitis pigmentosa 76, MIM#617123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 PNPLA6 Zornitza Stark reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24355708, 25033069; Phenotypes: Boucher-Neuhauser syndrome, MIM#215470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 PLK4 Zornitza Stark reviewed gene: PLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25344692, 25320347, 27650967; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 PEX6 Zornitza Stark gene: PEX6 was added
gene: PEX6 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: PEX6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595
Phenotypes for gene: PEX6 were set to Heimler syndrome 2, MIM# 616617
Review for gene: PEX6 was set to GREEN
gene: PEX6 was marked as current diagnostic
Added comment: Heimler syndrome, which represents the mildest end of the peroxisomal biogenesis disorder spectrum, is a rare autosomal recessive disorder characterised by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, nail abnormalities, and retinitis pigmentosa. More than 5 unrelated families reported.
Sources: Expert list
Retinal disorders v2.20 PAX2 Zornitza Stark reviewed gene: PAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Papillorenal syndrome, MIM# 120330; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 P3H2 Zornitza Stark reviewed gene: P3H2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21885030, 24172257, 25469533; Phenotypes: Myopia, high, with cataract and vitreoretinal degeneration MIM#614292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.427 MPV17 Ivone Leong Publications for gene: MPV17 were set to
Intellectual disability v3.426 LAS1L Ivone Leong changed review comment from: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.; to: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. This gene is listed in OMIM and Gene2Phenotype with a relevant phenotype. In Gene2Phenotype it has been classified as probable course for the phenotype. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.
Intellectual disability v3.426 LAS1L Ivone Leong Classified gene: LAS1L as Amber List (moderate evidence)
Intellectual disability v3.426 LAS1L Ivone Leong Added comment: Comment on list classification: Based on the expert reviews and available evidence, this gene has been promoted from Red to Amber. As the ID severity in the second case in (PMID: 25644381) is unknown and the variant in 1 case reported by (PMID: 26358559) is predicted to be benign. Until there is further evidence this gene has been given an Amber rating.
Intellectual disability v3.426 LAS1L Ivone Leong Gene: las1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.425 LAS1L Ivone Leong Tag watchlist tag was added to gene: LAS1L.
Hypophosphataemia or rickets v2.7 ALPL Ivone Leong Phenotypes for gene: ALPL were changed from Hypophosphatasia, infantile, MIM# 241500 to Hypophosphatasia, infantile, 241500; Hypophosphatasia, childhood, 241500
Hypophosphataemia or rickets v2.6 SGK3 Ivone Leong Classified gene: SGK3 as Red List (low evidence)
Hypophosphataemia or rickets v2.6 SGK3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. As there is only 1 case there is not enough evidence to support a gene-disease assocation. This gene has been given a Red review.
Hypophosphataemia or rickets v2.6 SGK3 Ivone Leong Gene: sgk3 has been classified as Red List (Low Evidence).
Intellectual disability v3.425 NUP214 Arina Puzriakova Tag for-review tag was added to gene: NUP214.
Cytopenias and congenital anaemias v1.78 TINF2 Arina Puzriakova Phenotypes for gene: TINF2 were changed from Inherited Bone Marrow Failure Syndromes; Inherited Bone Marrow Failure Syndromes - Aplastic Anaemia; Revesz Syndrome; Dyskeratosis congenita, autosomal dominant 3, 613990; Revesz syndrome, 268130; Revesz Syndrome; Dyskeratosis congenita; Dyskeratosis Congenita, Dominant; Dyskeratosis Congenita, Autosomal Dominant, 3; DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT, 3 to Revesz syndrome 268130; Dyskeratosis congenita, autosomal dominant 3 613990
Cytopenia - NOT Fanconi anaemia v1.28 TINF2 Arina Puzriakova Phenotypes for gene: TINF2 were changed from Inherited Bone Marrow Failure Syndromes - Aplastic Anaemia; 268130 Revesz syndrome; Revesz Syndrome; Dyskeratosis Congenita, Autosomal Dominant, 3; DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT, 3; Dyskeratosis congenita; 613990 Dyskeratosis congenita, autosomal dominant 3; Dyskeratosis congenita, autosomal dominant 3, 613990; Revesz syndrome, 268130; Inherited Bone Marrow Failure Syndromes; Dyskeratosis Congenita, Dominant to Dyskeratosis congenita, autosomal dominant 3, 613990; Revesz syndrome, 268130; Inherited Bone Marrow Failure Syndromes - Aplastic Anaemia
Intellectual disability v3.425 TINF2 Arina Puzriakova Phenotypes for gene: TINF2 were changed from Dyskeratosis congenita, autosomal dominant 3 613990 to Dyskeratosis congenita, autosomal dominant 3, 613990; Revesz syndrome, 268130
Intracerebral calcification disorders v1.27 TINF2 Arina Puzriakova Phenotypes for gene: TINF2 were changed from Revesz syndrome, MIM# 268130 to Revesz syndrome, 268130
Intracerebral calcification disorders v1.26 TINF2 Arina Puzriakova Tag for-review was removed from gene: TINF2.
Intracerebral calcification disorders v1.26 TINF2 Arina Puzriakova Classified gene: TINF2 as Green List (high evidence)
Intracerebral calcification disorders v1.26 TINF2 Arina Puzriakova Gene: tinf2 has been classified as Green List (High Evidence).
Intracerebral calcification disorders v1.25 TINF2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Intracranial calcification is a feature of Revesz syndrome, and has been reported in literature in at least 4 unrelated cases with different variants in the TINF2 gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green on this panel - intracranial calcification is a feature of Revesz syndrome, and has been reported in literature in at least 4 unrelated cases with different variants in the TINF2 gene.
Intracerebral calcification disorders v1.25 FARSB Arina Puzriakova Tag for-review was removed from gene: FARSB.
Intracerebral calcification disorders v1.25 FARSB Arina Puzriakova Classified gene: FARSB as Green List (high evidence)
Intracerebral calcification disorders v1.25 FARSB Arina Puzriakova Gene: farsb has been classified as Green List (High Evidence).
Intracerebral calcification disorders v1.24 FARSB Arina Puzriakova changed review comment from: Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team), it was agreed that there is sufficient evidence/number of cases with the relevant phenotype to rate this gene Green at the next GMS panel update.; to: Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team), it was agreed that there is sufficient evidence/number of cases with the relevant phenotype to rate this gene Green.
Familial pulmonary fibrosis v1.13 FARSB Arina Puzriakova changed review comment from: Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team), it was agreed that there is sufficient evidence/number of cases with the relevant phenotype to rate this gene Green at the next GMS panel update.; to: Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team), it was agreed that there is sufficient evidence/number of cases with the relevant phenotype to rate this gene Green.
Familial pulmonary fibrosis v1.13 FARSB Arina Puzriakova Tag for-review was removed from gene: FARSB.
Familial pulmonary fibrosis v1.13 FARSB Arina Puzriakova Classified gene: FARSB as Green List (high evidence)
Familial pulmonary fibrosis v1.13 FARSB Arina Puzriakova Gene: farsb has been classified as Green List (High Evidence).
Familial pulmonary fibrosis v1.12 FARSB Arina Puzriakova Classified gene: FARSB as Amber List (moderate evidence)
Familial pulmonary fibrosis v1.12 FARSB Arina Puzriakova Gene: farsb has been classified as Amber List (Moderate Evidence).
Familial pulmonary fibrosis v1.11 FARSB Arina Puzriakova Tag for-review tag was added to gene: FARSB.
Familial pulmonary fibrosis v1.11 FARSB Arina Puzriakova changed review comment from: Comment on list classification: Rating Green following consultation with the clinical team - sufficient number of cases with the relevant phenotype.; to: Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team), it was agreed that there is sufficient evidence/number of cases with the relevant phenotype to rate this gene Green at the next GMS panel update.
Limb disorders v2.14 HDAC4 Sarah Leigh Publications for gene: HDAC4 were set to 20691407; 15521982; 19365831
Intracerebral calcification disorders v1.24 FARSB Arina Puzriakova Classified gene: FARSB as Amber List (moderate evidence)
Intracerebral calcification disorders v1.24 FARSB Arina Puzriakova Added comment: Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team), it was agreed that there is sufficient evidence/number of cases with the relevant phenotype to rate this gene Green at the next GMS panel update.
Intracerebral calcification disorders v1.24 FARSB Arina Puzriakova Gene: farsb has been classified as Amber List (Moderate Evidence).
Intracerebral calcification disorders v1.23 FARSB Arina Puzriakova Tag for-review tag was added to gene: FARSB.
Intracerebral calcification disorders v1.23 FARSB Arina Puzriakova Deleted their comment
Intracerebral calcification disorders v1.23 TINF2 Arina Puzriakova changed review comment from: Comment on list classification: Intracranial calcification is a feature of Revesz syndrome, and has been reported in literature in at least 4 unrelated cases with different variants in the TINF2 gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Intracranial calcification is a feature of Revesz syndrome, and has been reported in literature in at least 4 unrelated cases with different variants in the TINF2 gene.
Intracerebral calcification disorders v1.23 TINF2 Arina Puzriakova Classified gene: TINF2 as Amber List (moderate evidence)
Intracerebral calcification disorders v1.23 TINF2 Arina Puzriakova Added comment: Comment on list classification: Intracranial calcification is a feature of Revesz syndrome, and has been reported in literature in at least 4 unrelated cases with different variants in the TINF2 gene.
Intracerebral calcification disorders v1.23 TINF2 Arina Puzriakova Gene: tinf2 has been classified as Amber List (Moderate Evidence).
Intracerebral calcification disorders v1.22 TINF2 Arina Puzriakova Tag for-review tag was added to gene: TINF2.
Intracerebral calcification disorders v1.22 TINF2 Arina Puzriakova Added comment: Comment on publications: Added publications to support association with this phenotype.
Intracerebral calcification disorders v1.22 TINF2 Arina Puzriakova Publications for gene: TINF2 were set to 21477109; 18252230
Skeletal dysplasia v2.22 ISCA-37394-Loss Sarah Leigh Publications for Region: ISCA-37394-Loss were set to 25402011; 23188045
Retinal disorders v2.20 TINF2 Arina Puzriakova Publications for gene: TINF2 were set to 18252230; 21477109; 25067791; 28095086; 28866069; 29749240; 30478948
Retinal disorders v2.19 TINF2 Arina Puzriakova edited their review of gene: TINF2: Changed publications: 18252230, 21477109, 28095086, 28866069, 29749240, 30478948
Intellectual disability v3.424 HDAC4 Sarah Leigh Publications for gene: HDAC4 were set to
Retinal disorders v2.19 TINF2 Arina Puzriakova Classified gene: TINF2 as Amber List (moderate evidence)
Retinal disorders v2.19 TINF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.
Retinal disorders v2.19 TINF2 Arina Puzriakova Gene: tinf2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.18 TINF2 Arina Puzriakova changed review comment from: Bilateral exudative retinopathy is a defining feature of Revesz syndrome, in addition to other manifestations such as bone marrow failure, intracranial calcification and cerebellar hypoplasia. Multiple (>3) unrelated cases reported in literature with retinal findings.
Sources: Literature; to: Bilateral exudative retinopathy is a defining feature of Revesz syndrome, in addition to other manifestations such as bone marrow failure, intracranial calcification and cerebellar hypoplasia. Multiple (>3) unrelated cases reported in literature with retinal findings.

Retinopathy can be the first presenting feature in patients with Revesz syndrome and so inclusion of TINF2 on this panel is likely to be of benefit.
Sources: Literature
Retinal disorders v2.18 TINF2 Arina Puzriakova gene: TINF2 was added
gene: TINF2 was added to Retinal disorders. Sources: Literature
for-review tags were added to gene: TINF2.
Mode of inheritance for gene: TINF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TINF2 were set to 18252230; 21477109; 25067791; 28095086; 28866069; 29749240; 30478948
Phenotypes for gene: TINF2 were set to Revesz syndrome, 268130
Review for gene: TINF2 was set to GREEN
Added comment: Bilateral exudative retinopathy is a defining feature of Revesz syndrome, in addition to other manifestations such as bone marrow failure, intracranial calcification and cerebellar hypoplasia. Multiple (>3) unrelated cases reported in literature with retinal findings.
Sources: Literature
Intellectual disability v3.423 TINF2 Arina Puzriakova Classified gene: TINF2 as Red List (low evidence)
Intellectual disability v3.423 TINF2 Arina Puzriakova Added comment: Comment on list classification: Although DD can be a feature, the condition is expected to present in a syndromic manner with cytopenia, cerebellar hypoplasia and retinopathy representing key characteristics. It is expected that these indications should be sufficient for detecting cases - TINF2 is already Green on the relevant panels.

Calling variants in this gene in a cohort of ID patients is therefore unlikely to be of benefit and so the rating has been kept Red.
Intellectual disability v3.423 TINF2 Arina Puzriakova Gene: tinf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.421 ZMPSTE24 Arina Puzriakova Source Expert Review Red was added to ZMPSTE24.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ZIC3 Arina Puzriakova Source Expert Review Red was added to ZIC3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 XPC Arina Puzriakova Source Expert Review Red was added to XPC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WRAP53 Arina Puzriakova Source Expert Review Red was added to WRAP53.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WNT7A Arina Puzriakova Source Expert Review Red was added to WNT7A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WNT3 Arina Puzriakova Source Expert Review Red was added to WNT3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WNT10B Arina Puzriakova Source Expert Review Red was added to WNT10B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WDR35 Arina Puzriakova Source Expert Review Red was added to WDR35.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WDR34 Arina Puzriakova Source Expert Review Red was added to WDR34.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 WDR19 Arina Puzriakova Source Expert Review Red was added to WDR19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 VSX2 Arina Puzriakova Source Expert Review Red was added to VSX2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 UVSSA Arina Puzriakova Source Expert Review Red was added to UVSSA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 USB1 Arina Puzriakova Source Expert Review Red was added to USB1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 UROS Arina Puzriakova Source Expert Review Red was added to UROS.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 UGT1A1 Arina Puzriakova Source Expert Review Red was added to UGT1A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TYRP1 Arina Puzriakova Source Expert Review Red was added to TYRP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TYR Arina Puzriakova Source Expert Review Red was added to TYR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TXNL4A Arina Puzriakova Source Expert Review Red was added to TXNL4A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TUBA8 Arina Puzriakova Source Expert Review Red was added to TUBA8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TSHR Arina Puzriakova Source Expert Review Red was added to TSHR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRPV4 Arina Puzriakova Source Expert Review Red was added to TRPV4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRPS1 Arina Puzriakova Source Expert Review Red was added to TRPS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRPM1 Arina Puzriakova Source Expert Review Red was added to TRPM1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRIP11 Arina Puzriakova Source Expert Review Red was added to TRIP11.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TRAPPC2 Arina Puzriakova Source Expert Review Red was added to TRAPPC2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TP63 Arina Puzriakova Source Expert Review Red was added to TP63.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TMPRSS6 Arina Puzriakova Source Expert Review Red was added to TMPRSS6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TMEM126B Arina Puzriakova Source Expert Review Red was added to TMEM126B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TGFB3 Arina Puzriakova Source Expert Review Red was added to TGFB3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TGFB2 Arina Puzriakova Source Expert Review Red was added to TGFB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TEK Arina Puzriakova Source Expert Review Red was added to TEK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TCF12 Arina Puzriakova Source Expert Review Red was added to TCF12.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBXAS1 Arina Puzriakova Source Expert Review Red was added to TBXAS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX5 Arina Puzriakova Source Expert Review Red was added to TBX5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX4 Arina Puzriakova Source Expert Review Red was added to TBX4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX3 Arina Puzriakova Source Expert Review Red was added to TBX3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX22 Arina Puzriakova Source Expert Review Red was added to TBX22.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX20 Arina Puzriakova Source Expert Review Red was added to TBX20.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TBX15 Arina Puzriakova Source Expert Review Red was added to TBX15.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 TAB2 Arina Puzriakova Source Expert Review Red was added to TAB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 STAR Arina Puzriakova Source Expert Review Red was added to STAR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SRY Arina Puzriakova Source Expert Review Red was added to SRY.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SPEG Arina Puzriakova Source Expert Review Red was added to SPEG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SPAG1 Arina Puzriakova Source Expert Review Red was added to SPAG1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SOX17 Arina Puzriakova Source Expert Review Red was added to SOX17.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SMCHD1 Arina Puzriakova Source Expert Review Red was added to SMCHD1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 SCN4A Arina Puzriakova Source Expert Review Red was added to SCN4A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RUNX2 Arina Puzriakova Source Expert Review Red was added to RUNX2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RSPO4 Arina Puzriakova Source Expert Review Red was added to RSPO4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RSPH3 Arina Puzriakova Source Expert Review Red was added to RSPH3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RSPH1 Arina Puzriakova Source Expert Review Red was added to RSPH1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RPS19 Arina Puzriakova Source Expert Review Red was added to RPS19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RPGRIP1 Arina Puzriakova Source Expert Review Red was added to RPGRIP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RPE65 Arina Puzriakova Source Expert Review Red was added to RPE65.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ROBO3 Arina Puzriakova Source Expert Review Red was added to ROBO3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 RETREG1 Arina Puzriakova Source Expert Review Red was added to RETREG1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PGM1 Arina Puzriakova Source Expert Review Red was added to PGM1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PDE6G Arina Puzriakova Source Expert Review Red was added to PDE6G.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PAX9 Arina Puzriakova Source Expert Review Red was added to PAX9.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PAX3 Arina Puzriakova Source Expert Review Red was added to PAX3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 PAPSS2 Arina Puzriakova Source Expert Review Red was added to PAPSS2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 OTULIN Arina Puzriakova Source Expert Review Red was added to OTULIN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 OTOGL Arina Puzriakova Source Expert Review Red was added to OTOGL.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ORC6 Arina Puzriakova Source Expert Review Red was added to ORC6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NRXN2 Arina Puzriakova Source Expert Review Red was added to NRXN2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NR5A1 Arina Puzriakova Source Expert Review Red was added to NR5A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NR2F2 Arina Puzriakova Source Expert Review Red was added to NR2F2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NPR2 Arina Puzriakova Source Expert Review Red was added to NPR2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NPHS1 Arina Puzriakova Source Expert Review Red was added to NPHS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NPHP4 Arina Puzriakova Source Expert Review Red was added to NPHP4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NOTCH2 Arina Puzriakova Source Expert Review Red was added to NOTCH2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NOG Arina Puzriakova Source Expert Review Red was added to NOG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NODAL Arina Puzriakova Source Expert Review Red was added to NODAL.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NMNAT1 Arina Puzriakova Source Expert Review Red was added to NMNAT1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NKX3-2 Arina Puzriakova Source Expert Review Red was added to NKX3-2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 NEK1 Arina Puzriakova Source Expert Review Red was added to NEK1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYO5B Arina Puzriakova Source Expert Review Red was added to MYO5B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYH9 Arina Puzriakova Source Expert Review Red was added to MYH9.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYH8 Arina Puzriakova Source Expert Review Red was added to MYH8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MYH6 Arina Puzriakova Source Expert Review Red was added to MYH6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MSX2 Arina Puzriakova Source Expert Review Red was added to MSX2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MSX1 Arina Puzriakova Source Expert Review Red was added to MSX1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MNX1 Arina Puzriakova Source Expert Review Red was added to MNX1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MMP13 Arina Puzriakova Source Expert Review Red was added to MMP13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MFRP Arina Puzriakova Source Expert Review Red was added to MFRP.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MESP2 Arina Puzriakova Source Expert Review Red was added to MESP2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MC2R Arina Puzriakova Source Expert Review Red was added to MC2R.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MATN3 Arina Puzriakova Source Expert Review Red was added to MATN3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 MAP3K1 Arina Puzriakova Source Expert Review Red was added to MAP3K1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LTBP3 Arina Puzriakova Source Expert Review Red was added to LTBP3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LTBP2 Arina Puzriakova Source Expert Review Red was added to LTBP2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LRRC6 Arina Puzriakova Source Expert Review Red was added to LRRC6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LRP4 Arina Puzriakova Source Expert Review Red was added to LRP4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LMX1B Arina Puzriakova Source Expert Review Red was added to LMX1B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LMNA Arina Puzriakova Source Expert Review Red was added to LMNA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LHX4 Arina Puzriakova Source Expert Review Red was added to LHX4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LHX3 Arina Puzriakova Source Expert Review Red was added to LHX3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LFNG Arina Puzriakova Source Expert Review Red was added to LFNG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LEMD3 Arina Puzriakova Source Expert Review Red was added to LEMD3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 LDB3 Arina Puzriakova Source Expert Review Red was added to LDB3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KLHL40 Arina Puzriakova Source Expert Review Red was added to KLHL40.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KLF1 Arina Puzriakova Source Expert Review Red was added to KLF1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KIT Arina Puzriakova Source Expert Review Red was added to KIT.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KIRREL3 Arina Puzriakova Source Expert Review Red was added to KIRREL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KIF22 Arina Puzriakova Source Expert Review Red was added to KIF22.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KCTD1 Arina Puzriakova Source Expert Review Red was added to KCTD1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KCNQ1 Arina Puzriakova Source Expert Review Red was added to KCNQ1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KCND3 Arina Puzriakova Source Expert Review Red was added to KCND3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 KBTBD13 Arina Puzriakova Source Expert Review Red was added to KBTBD13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 JAK3 Arina Puzriakova Source Expert Review Red was added to JAK3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 JAGN1 Arina Puzriakova Source Expert Review Red was added to JAGN1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 JAG1 Arina Puzriakova Source Expert Review Red was added to JAG1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IRF6 Arina Puzriakova Source Expert Review Red was added to IRF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 INPPL1 Arina Puzriakova Source Expert Review Red was added to INPPL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IMPAD1 Arina Puzriakova Source Expert Review Red was added to IMPAD1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IL11RA Arina Puzriakova Source Expert Review Red was added to IL11RA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IHH Arina Puzriakova Source Expert Review Red was added to IHH.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IGF2 Arina Puzriakova Source Expert Review Red was added to IGF2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IFT80 Arina Puzriakova Source Expert Review Red was added to IFT80.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IFT122 Arina Puzriakova Source Expert Review Red was added to IFT122.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 IFITM5 Arina Puzriakova Source Expert Review Red was added to IFITM5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HYDIN Arina Puzriakova Source Expert Review Red was added to HYDIN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HYAL1 Arina Puzriakova Source Expert Review Red was added to HYAL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HSF4 Arina Puzriakova Source Expert Review Red was added to HSF4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HSD3B7 Arina Puzriakova Source Expert Review Red was added to HSD3B7.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HR Arina Puzriakova Source Expert Review Red was added to HR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HPSE2 Arina Puzriakova Source Expert Review Red was added to HPSE2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HPS1 Arina Puzriakova Source Expert Review Red was added to HPS1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HPGD Arina Puzriakova Source Expert Review Red was added to HPGD.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HOXD13 Arina Puzriakova Source Expert Review Red was added to HOXD13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HOXC13 Arina Puzriakova Source Expert Review Red was added to HOXC13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HOXA13 Arina Puzriakova Source Expert Review Red was added to HOXA13.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HNF4A Arina Puzriakova Source Expert Review Red was added to HNF4A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 HMGCS2 Arina Puzriakova Source Expert Review Red was added to HMGCS2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GUCY2C Arina Puzriakova Source Expert Review Red was added to GUCY2C.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GRM6 Arina Puzriakova Source Expert Review Red was added to GRM6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GRHL3 Arina Puzriakova Source Expert Review Red was added to GRHL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GPR179 Arina Puzriakova Source Expert Review Red was added to GPR179.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GNAI3 Arina Puzriakova Source Expert Review Red was added to GNAI3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GLMN Arina Puzriakova Source Expert Review Red was added to GLMN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GLE1 Arina Puzriakova Source Expert Review Red was added to GLE1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GJA8 Arina Puzriakova Source Expert Review Red was added to GJA8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GJA3 Arina Puzriakova Source Expert Review Red was added to GJA3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GJA1 Arina Puzriakova Source Expert Review Red was added to GJA1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GHR Arina Puzriakova Source Expert Review Red was added to GHR.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GDF6 Arina Puzriakova Source Expert Review Red was added to GDF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GDF5 Arina Puzriakova Source Expert Review Red was added to GDF5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GATA4 Arina Puzriakova Source Expert Review Red was added to GATA4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GATA2 Arina Puzriakova Source Expert Review Red was added to GATA2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GAS8 Arina Puzriakova Source Expert Review Red was added to GAS8.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GALK1 Arina Puzriakova Source Expert Review Red was added to GALK1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 GAA Arina Puzriakova Source Expert Review Red was added to GAA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FZD6 Arina Puzriakova Source Expert Review Red was added to FZD6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FYCO1 Arina Puzriakova Source Expert Review Red was added to FYCO1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FXN Arina Puzriakova Source Expert Review Red was added to FXN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FTL Arina Puzriakova Source Expert Review Red was added to FTL.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXN1 Arina Puzriakova Source Expert Review Red was added to FOXN1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXF1 Arina Puzriakova Source Expert Review Red was added to FOXF1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXE3 Arina Puzriakova Source Expert Review Red was added to FOXE3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXE1 Arina Puzriakova Source Expert Review Red was added to FOXE1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXC2 Arina Puzriakova Source Expert Review Red was added to FOXC2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FOXC1 Arina Puzriakova Source Expert Review Red was added to FOXC1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FLT4 Arina Puzriakova Source Expert Review Red was added to FLT4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FLNB Arina Puzriakova Source Expert Review Red was added to FLNB.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FKBP14 Arina Puzriakova Source Expert Review Red was added to FKBP14.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FHL1 Arina Puzriakova Source Expert Review Red was added to FHL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FGF3 Arina Puzriakova Source Expert Review Red was added to FGF3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FGF10 Arina Puzriakova Source Expert Review Red was added to FGF10.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FBXW4 Arina Puzriakova Source Expert Review Red was added to FBXW4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FBP1 Arina Puzriakova Source Expert Review Red was added to FBP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FBN1 Arina Puzriakova Source Expert Review Red was added to FBN1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FAM20A Arina Puzriakova Source Expert Review Red was added to FAM20A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 FAM161A Arina Puzriakova Source Expert Review Red was added to FAM161A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EYA1 Arina Puzriakova Source Expert Review Red was added to EYA1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EVC2 Arina Puzriakova Source Expert Review Red was added to EVC2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EVC Arina Puzriakova Source Expert Review Red was added to EVC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ERF Arina Puzriakova Source Expert Review Red was added to ERF.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ERCC4 Arina Puzriakova Source Expert Review Red was added to ERCC4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EOGT Arina Puzriakova Source Expert Review Red was added to EOGT.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ENPP1 Arina Puzriakova Source Expert Review Red was added to ENPP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EDNRA Arina Puzriakova Source Expert Review Red was added to EDNRA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 EDA Arina Puzriakova Source Expert Review Red was added to EDA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ECEL1 Arina Puzriakova Source Expert Review Red was added to ECEL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DYNC2H1 Arina Puzriakova Source Expert Review Red was added to DYNC2H1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DVL1 Arina Puzriakova Source Expert Review Red was added to DVL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DSTYK Arina Puzriakova Source Expert Review Red was added to DSTYK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DSPP Arina Puzriakova Source Expert Review Red was added to DSPP.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DNAAF4 Arina Puzriakova Source Expert Review Red was added to DNAAF4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DNAAF3 Arina Puzriakova Source Expert Review Red was added to DNAAF3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DMP1 Arina Puzriakova Source Expert Review Red was added to DMP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DLL4 Arina Puzriakova Source Expert Review Red was added to DLL4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DLL3 Arina Puzriakova Source Expert Review Red was added to DLL3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DDB2 Arina Puzriakova Source Expert Review Red was added to DDB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 DCC Arina Puzriakova Source Expert Review Red was added to DCC.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CYP1B1 Arina Puzriakova Source Expert Review Red was added to CYP1B1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CTSK Arina Puzriakova Source Expert Review Red was added to CTSK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CTSF Arina Puzriakova Source Expert Review Red was added to CTSF.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CTNS Arina Puzriakova Source Expert Review Red was added to CTNS.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYGD Arina Puzriakova Source Expert Review Red was added to CRYGD.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBB3 Arina Puzriakova Source Expert Review Red was added to CRYBB3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBB2 Arina Puzriakova Source Expert Review Red was added to CRYBB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBB1 Arina Puzriakova Source Expert Review Red was added to CRYBB1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYBA1 Arina Puzriakova Source Expert Review Red was added to CRYBA1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRYAA Arina Puzriakova Source Expert Review Red was added to CRYAA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRX Arina Puzriakova Source Expert Review Red was added to CRX.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CRB1 Arina Puzriakova Source Expert Review Red was added to CRB1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COMP Arina Puzriakova Source Expert Review Red was added to COMP.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL9A3 Arina Puzriakova Source Expert Review Red was added to COL9A3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL9A2 Arina Puzriakova Source Expert Review Red was added to COL9A2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL9A1 Arina Puzriakova Source Expert Review Red was added to COL9A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL6A1 Arina Puzriakova Source Expert Review Red was added to COL6A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL4A4 Arina Puzriakova Source Expert Review Red was added to COL4A4.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL4A3 Arina Puzriakova Source Expert Review Red was added to COL4A3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL2A1 Arina Puzriakova Source Expert Review Red was added to COL2A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL1A1 Arina Puzriakova Source Expert Review Red was added to COL1A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL18A1 Arina Puzriakova Source Expert Review Red was added to COL18A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL11A1 Arina Puzriakova Source Expert Review Red was added to COL11A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 COL10A1 Arina Puzriakova Source Expert Review Red was added to COL10A1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CLDN19 Arina Puzriakova Source Expert Review Red was added to CLDN19.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CLCN7 Arina Puzriakova Source Expert Review Red was added to CLCN7.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CIB2 Arina Puzriakova Source Expert Review Red was added to CIB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHUK Arina Puzriakova Source Expert Review Red was added to CHUK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHSY1 Arina Puzriakova Source Expert Review Red was added to CHSY1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHST3 Arina Puzriakova Source Expert Review Red was added to CHST3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHRNG Arina Puzriakova Source Expert Review Red was added to CHRNG.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHRDL1 Arina Puzriakova Source Expert Review Red was added to CHRDL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CHM Arina Puzriakova Source Expert Review Red was added to CHM.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CDH3 Arina Puzriakova Source Expert Review Red was added to CDH3.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CDH23 Arina Puzriakova Source Expert Review Red was added to CDH23.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCT5 Arina Puzriakova Source Expert Review Red was added to CCT5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCNO Arina Puzriakova Source Expert Review Red was added to CCNO.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC65 Arina Puzriakova Source Expert Review Red was added to CCDC65.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC40 Arina Puzriakova Source Expert Review Red was added to CCDC40.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC114 Arina Puzriakova Source Expert Review Red was added to CCDC114.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 CCDC103 Arina Puzriakova Source Expert Review Red was added to CCDC103.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 C4orf26 Arina Puzriakova Source Expert Review Red was added to C4orf26.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 C2orf71 Arina Puzriakova Source Expert Review Red was added to C2orf71.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 C19orf12 Arina Puzriakova Source Expert Review Red was added to C19orf12.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BMPR1B Arina Puzriakova Source Expert Review Red was added to BMPR1B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BMPER Arina Puzriakova Source Expert Review Red was added to BMPER.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BICD2 Arina Puzriakova Source Expert Review Red was added to BICD2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BHLHA9 Arina Puzriakova Source Expert Review Red was added to BHLHA9.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BGN Arina Puzriakova Source Expert Review Red was added to BGN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 BFSP2 Arina Puzriakova Source Expert Review Red was added to BFSP2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ATP6V1B1 Arina Puzriakova Source Expert Review Red was added to ATP6V1B1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.421 ARHGEF6 Arina Puzriakova Source Expert Review Red was added to ARHGEF6.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Retinal disorders v2.17 NEUROD1 Zornitza Stark reviewed gene: NEUROD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25477324, 25684977, 22784109, 29521454; Phenotypes: Retinitis pigmentosa, Retinopathy, Permanent neonatal diabetes; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 MTTP Zornitza Stark reviewed gene: MTTP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Abetalipoproteinemia, MIM# 200100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 MSTO1 Zornitza Stark gene: MSTO1 was added
gene: MSTO1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: MSTO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSTO1 were set to 29339779; 28544275
Phenotypes for gene: MSTO1 were set to Myopathy, mitochondrial, and ataxia MIM#617675
Review for gene: MSTO1 was set to GREEN
Added comment: Pigmentary retinopathy reported as a feature of the condition in at least 3 unrelated cases with biallelic variants.
Sources: Expert list
Retinal disorders v2.17 MMACHC Zornitza Stark gene: MMACHC was added
gene: MMACHC was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: MMACHC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMACHC were set to 28481040
Phenotypes for gene: MMACHC were set to Methylmalonic aciduria and homocystinuria, cblC type MIM#277400
Review for gene: MMACHC was set to GREEN
Added comment: Maculopathy/pigmentary retinopathy reported as a feature of the condition in at least 9 cases.
Sources: Expert list
Retinal disorders v2.17 LAMA1 Zornitza Stark reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Poretti-Boltshauser syndrome, MIM# 615960; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 IFT81 Zornitza Stark reviewed gene: IFT81: Rating: AMBER; Mode of pathogenicity: None; Publications: 28460050, 26275418, 27666822, 32783357; Phenotypes: Short-rib thoracic dysplasia 19 with or without polydactyly, MIM# 617895; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 IFT74 Zornitza Stark gene: IFT74 was added
gene: IFT74 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT74 were set to 27486776; 32144365
Phenotypes for gene: IFT74 were set to Bardet-Biedl syndrome 20, MIM# 617119
Review for gene: IFT74 was set to GREEN
gene: IFT74 was marked as current diagnostic
Added comment: Two families reported with BBS, supportive zebrafish model.
Sources: Expert list
Retinal disorders v2.17 IFT27 Zornitza Stark reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: None; Publications: 24488770, 30761183, 26763875, 25443296; Phenotypes: Bardet-Biedl syndrome 19, MIM#615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Retinal disorders v2.17 IFT172 Zornitza Stark reviewed gene: IFT172: Rating: GREEN; Mode of pathogenicity: None; Publications: 25168386, 29659833; Phenotypes: Retinitis pigmentosa 71, MIM# 616394; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 HK1 Zornitza Stark changed review comment from: Subsequent reported families are Asian, but with same recurrent missense. I am not convinced this is founder effect. Gene is associated with multiple phenotypes and this particular missense may have a specific effect that results in this particular phenotype. The variant is however present in 3 hets in gnomad (2 Asian, 1 European). This frequency may be compatible with AD retinitis pigmentosa.; to: Subsequent reported families are Asian, but with same recurrent missense. I am not convinced this is founder effect. Gene is associated with multiple phenotypes and this particular missense may have a specific effect that results in this particular phenotype. The variant is however present in 3 hets in gnomad (2 Asian, 1 European). This frequency may be compatible with AD retinitis pigmentosa.

However, also note PMID 30778173, where other mono-allelic variants have been linked to a neurodevelopmental disorder which includes visual impairment, and for this reason Green rating on this panel may still be appropriate.
Retinal disorders v2.17 HK1 Zornitza Stark edited their review of gene: HK1: Changed rating: GREEN; Changed publications: 25316723, 25190649, 31621442, 32814480, 30778173
Retinal disorders v2.17 HK1 Zornitza Stark reviewed gene: HK1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25316723, 25190649, 31621442, 32814480; Phenotypes: Retinitis pigmentosa 79, MIM# 617460; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.17 HARS Zornitza Stark reviewed gene: HARS: Rating: RED; Mode of pathogenicity: None; Publications: 22279524; Phenotypes: Usher syndrome type 3B, MIM# 614504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.21 GZF1 Zornitza Stark reviewed gene: GZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33009817; Phenotypes: Joint laxity, short stature, and myopia, MIM# 617662, Larsen-like syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Retinal disorders v2.17 GRN Zornitza Stark reviewed gene: GRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 31855245, 28404863, 30922528; Phenotypes: Ceroid lipofuscinosis, neuronal, 11, OMIM #614706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 GNB3 Zornitza Stark reviewed gene: GNB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27063057, 17065478; Phenotypes: Night blindness, congenital stationary, type 1H, MIM# 617024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.420 ITFG2 Konstantinos Varvagiannis gene: ITFG2 was added
gene: ITFG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Penetrance for gene: ITFG2 were set to Complete
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51).

Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS.

Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)].

As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306).

Please consider inclusion in the ID panel with amber rating, pending further details.
Sources: Literature
Intellectual disability v3.420 USP7 Konstantinos Varvagiannis edited their review of gene: USP7: Changed publications: 26365382, 19946331, 33012787
Intellectual disability v3.420 USP7 Konstantinos Varvagiannis changed review comment from: Please consider also PMID : 33012787 for Green rating (several cases reported).; to: Please consider also PMID : 33012787 for Green rating (several cases reported to date).
Intellectual disability v3.420 USP7 Konstantinos Varvagiannis commented on gene: USP7: Please consider also PMID : 33012787 for Green rating (several cases reported).
Intellectual disability v3.420 SHMT2 Konstantinos Varvagiannis gene: SHMT2 was added
gene: SHMT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Penetrance for gene: SHMT2 were set to Complete
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).

Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc.
Sources: Literature
Retinal disorders v2.17 CTSF Zornitza Stark gene: CTSF was added
gene: CTSF was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: CTSF was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CTSF were set to Ceroid lipofuscinosis, neuronal, 13, Kufs type OMIM #615362
Review for gene: CTSF was set to GREEN
Added comment: Retinal degeneration is a feature.
Sources: Expert list
Retinal disorders v2.17 CTNNA1 Zornitza Stark reviewed gene: CTNNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26691986; Phenotypes: Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.17 CTC1 Zornitza Stark gene: CTC1 was added
gene: CTC1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: CTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTC1 were set to 22267198
Phenotypes for gene: CTC1 were set to Cerebroretinal microangiopathy with calcifications and cysts MIM#612199
Review for gene: CTC1 was set to GREEN
gene: CTC1 was marked as current diagnostic
Added comment: Retinopathy is a feature of the condition. At least 10 families reported.
Sources: Expert list
Retinal disorders v2.17 CIB2 Zornitza Stark reviewed gene: CIB2: Rating: RED; Mode of pathogenicity: None; Publications: 23023331, 23023331, 26173970, 26473954, 27344577, 26226137, 26445815; Phenotypes: Usher syndrome, type IJ 614869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 CEP250 Zornitza Stark reviewed gene: CEP250: Rating: GREEN; Mode of pathogenicity: None; Publications: 24780881, 29718797, 30459346; Phenotypes: Cone-rod dystrophy and hearing loss 2, MIM# 618358; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 CA4 Zornitza Stark reviewed gene: CA4: Rating: RED; Mode of pathogenicity: None; Publications: 15563508, 15090652, 17652713, 16260723; Phenotypes: Retinitis pigmentosa 17, MIM# 600852; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.17 ARL13B Zornitza Stark reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18674751, 30573647, 25138100, 29255182; Phenotypes: Joubert syndrome 8 MIM#612291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 AP3B2 Zornitza Stark gene: AP3B2 was added
gene: AP3B2 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: AP3B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP3B2 were set to 27889060
Phenotypes for gene: AP3B2 were set to Early-onset epileptic encephalopathy with optic atrophy
Review for gene: AP3B2 was set to GREEN
Added comment: 8 different families reported with EE - poor vision reported in all, specifically optic pallor 4/6, and retinal pigment changes in 2/6.
Sources: Expert list
Retinal disorders v2.17 ALPK1 Zornitza Stark gene: ALPK1 was added
gene: ALPK1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to 30967659; 31939038
Phenotypes for gene: ALPK1 were set to ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache
Review for gene: ALPK1 was set to GREEN
gene: ALPK1 was marked as current diagnostic
Added comment: Six unrelated families reported with same recurrent missense variant c.710C>T, (p.Thr237Met). Pancytopaenia and recurrent infections present in some.
Sources: Expert list
Retinal disorders v2.17 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29181157, 26539208, 30252181, 30389403, 32219868, 32600459, 32548275; Phenotypes: Optic atrophy 12, MIM# 618977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.17 ACBD5 Zornitza Stark changed review comment from: 2 families reported and supporting in vitro functional assays demonstrating ACBD5 deficiency leading to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 27799409: 1 individual who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. Functional assay supports ACBD5 deficiency leads to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 23105016: 1 family retinal dystrophy.; to: 2 families reported and supporting in vitro functional assays demonstrating ACBD5 deficiency leading to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 27799409: 1 individual who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. Functional assay supports ACBD5 deficiency leads to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 23105016: 1 family with retinal dystrophy.
Retinal disorders v2.17 ACBD5 Zornitza Stark reviewed gene: ACBD5: Rating: AMBER; Mode of pathogenicity: None; Publications: 27799409, 23105016; Phenotypes: Retinal dystrophy with leukodystrophy (MIM#618863); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.17 ABCC6 Zornitza Stark reviewed gene: ABCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudoxanthoma elasticum, MIM#264800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.420 ABCB11 Arina Puzriakova Classified gene: ABCB11 as Red List (low evidence)
Intellectual disability v3.420 ABCB11 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.420 ABCB11 Arina Puzriakova Gene: abcb11 has been classified as Red List (Low Evidence).
Intellectual disability v3.419 ACAN Arina Puzriakova Classified gene: ACAN as Red List (low evidence)
Intellectual disability v3.419 ACAN Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red in context of the review by Konstantinos Varvagiannis
Intellectual disability v3.419 ACAN Arina Puzriakova Gene: acan has been classified as Red List (Low Evidence).
Intellectual disability v3.418 ATP8B1 Arina Puzriakova Classified gene: ATP8B1 as Red List (low evidence)
Intellectual disability v3.418 ATP8B1 Arina Puzriakova Gene: atp8b1 has been classified as Red List (Low Evidence).
Intellectual disability v3.417 ATP8B1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Clefting v2.5 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Clefting v2.5 KAT5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Two unrelated cases reported in PMID:32822602 and additional cases required before inclusion on a diagnostic panel.

Rating Amber, awaiting further publications/clinical evidence to corroborate the association with this phenotype.
Clefting v2.5 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.170 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Early onset or syndromic epilepsy v2.169 KAT5 Arina Puzriakova Publications for gene: KAT5 were set to
Early onset or syndromic epilepsy v2.168 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.417 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.416 KAT5 Arina Puzriakova Publications for gene: KAT5 were set to
Intellectual disability v3.415 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.415 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.166 KAT5 Arina Puzriakova Tag for-review tag was added to gene: KAT5.
Intellectual disability v3.414 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Intellectual disability v3.414 KAT5 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.
Intellectual disability v3.414 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.413 KAT5 Arina Puzriakova Tag for-review tag was added to gene: KAT5.
Cytopenia - NOT Fanconi anaemia v1.27 RPS20 Arina Puzriakova Classified gene: RPS20 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.27 RPS20 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as currently only two unrelated cases reported with DBA in association with variants in the RPS20 gene (PMID:32790018).
Cytopenia - NOT Fanconi anaemia v1.27 RPS20 Arina Puzriakova Gene: rps20 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.20 SCAF4 Arina Puzriakova Classified gene: SCAF4 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.20 SCAF4 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next GMS panel update - sufficient number of unrelated cases presenting white matter anomalies associated with distinct variants in SCAF4
White matter disorders and cerebral calcification - childhood onset v1.20 SCAF4 Arina Puzriakova Gene: scaf4 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.19 SCAF4 Arina Puzriakova gene: SCAF4 was added
gene: SCAF4 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
for-review tags were added to gene: SCAF4.
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to 32730804
Phenotypes for gene: SCAF4 were set to SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on 23/09/2014), but is a probable gene SCAF4-related Neurodevelopmental Disorder in Gen2Phen.

PMID: 32730804 (2020) - At least 8 unrelated patients with likely pathogenic variants in SCAF4 and mild DD/ID, seizures behavioural abnormalities, and various skeletal, renal and cardiac anomalies. 7 de novo and 1 inherited variant. Brain MRIs were performed in five individuals
showing nonspecific white matter anomalies in three of them. One other individual was diagnosed with pontocerebellar hypoplasia and a thin corpus callosum.
Sources: Literature
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Classified gene: SCAF4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next GMS panel update - sufficient number of unrelated cases presenting seizures due to distinct variants in SCAF4
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.165 SCAF4 Arina Puzriakova gene: SCAF4 was added
gene: SCAF4 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: SCAF4.
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to 32730804
Phenotypes for gene: SCAF4 were set to SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on 23/09/2014), but is a probable gene SCAF4-related Neurodevelopmental Disorder in Gen2Phen.

PMID: 32730804 (2020) - At least 8 unrelated patients with likely pathogenic variants in SCAF4 and mild DD/ID, behavioural abnormalities, and various skeletal, renal and cardiac anomalies. 7 de novo and 1 inherited variant. Seizures occurred in 4 individuals (50%) and included myoclonic seizures in two and intractable seizures in one.
Sources: Literature
Intellectual disability v3.413 SCAF4 Arina Puzriakova Phenotypes for gene: SCAF4 were changed from to SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities
Intellectual disability v3.412 SCAF4 Arina Puzriakova Classified gene: SCAF4 as Amber List (moderate evidence)
Intellectual disability v3.412 SCAF4 Arina Puzriakova Added comment: Comment on list classification: At least 8 unrelated individuals reported in PMID:32730804 with a neurodevelopmental disorder characterised by DD/ID, mostly in the mild range (severe in only one individual).

Rating Amber in view of the mild ID presentation. This may be reviewed if further cases are reported with more severe manifestations of relevant phenotypes.
Intellectual disability v3.412 SCAF4 Arina Puzriakova Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.411 SCAF4 Arina Puzriakova commented on gene: SCAF4
Intellectual disability v3.411 SCAF4 Arina Puzriakova Publications for gene: SCAF4 were set to
Fetal anomalies v1.104 USP18 Arina Puzriakova Classified gene: USP18 as Amber List (moderate evidence)
Fetal anomalies v1.104 USP18 Arina Puzriakova Added comment: Comment on list classification: With addition of the recently reported case (PMID:31940699) there is now a total of three families with pseudo-TORCH syndrome due to biallelic variants in USP18 (two carrying the same founder variant).

A rating upgrade from Amber to Green should be considered and therefore this gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).
Fetal anomalies v1.104 USP18 Arina Puzriakova Gene: usp18 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.103 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Fetal anomalies v1.103 USP18 Arina Puzriakova reviewed gene: USP18: Rating: ; Mode of pathogenicity: None; Publications: 31940699; Phenotypes: Pseudo-TORCH syndrome 2, 617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.103 USP18 Arina Puzriakova Publications for gene: USP18 were set to
Fetal anomalies v1.102 USP18 Arina Puzriakova Phenotypes for gene: USP18 were changed from Severe pseudo-TORCH syndrome to Pseudo-TORCH syndrome 2, 617397
Fetal anomalies v1.101 USP18 Arina Puzriakova Tag treatable tag was added to gene: USP18.
Tag for-review tag was added to gene: USP18.
Hereditary ataxia and cerebellar anomalies, childhood onset v6.53 Arina Puzriakova Panel version has been signed off
Congenital disorders of glycosylation v2.15 GALNT2 Arina Puzriakova Classified gene: GALNT2 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.15 GALNT2 Arina Puzriakova Added comment: Comment on list classification: The rating of this gene should be reviewed at the date of next GMS panel update - there is sufficient evidence to rate this gene Green.
Congenital disorders of glycosylation v2.15 GALNT2 Arina Puzriakova Gene: galnt2 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v2.14 GALNT2 Arina Puzriakova Tag for-review tag was added to gene: GALNT2.
Cholestasis v1.38 PKHD1 Ivone Leong Phenotypes for gene: PKHD1 were changed from Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200 to Polycystic kidney disease 4, with or without hepatic disease, 263200
Cholestasis v1.37 NPHP3 Ivone Leong Phenotypes for gene: NPHP3 were changed from Renal-hepatic-pancreatic dysplasia 1, MIM# 208540 to Renal-hepatic-pancreatic dysplasia 1, 208540
Intellectual disability v3.410 NEDD4L Eleanor Williams changed review comment from: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation.; to: Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.

PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation. Seizures were reported in some but not all affected individuals.
Intellectual disability v3.410 NEDD4L Eleanor Williams Tag for-review tag was added to gene: NEDD4L.
Intellectual disability v3.410 NEDD4L Eleanor Williams Classified gene: NEDD4L as Amber List (moderate evidence)
Intellectual disability v3.410 NEDD4L Eleanor Williams Gene: nedd4l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.409 NEDD4L Eleanor Williams Classified gene: NEDD4L as Red List (low evidence)
Intellectual disability v3.409 NEDD4L Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases with a severe developmental delay phenotype for it to be rated green. It should therefore be reviewed at the next GMS update.
Intellectual disability v3.409 NEDD4L Eleanor Williams Gene: nedd4l has been classified as Red List (Low Evidence).
Intellectual disability v3.408 NEDD4L Eleanor Williams Phenotypes for gene: NEDD4L were changed from EPILEPTIC ENCEPHALOPATHY to Periventricular nodular heterotopia 7, 617201
Intellectual disability v3.408 NEDD4L Eleanor Williams Publications for gene: NEDD4L were set to 23934111
Intellectual disability v3.407 NEDD4L Eleanor Williams reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, 617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.407 NUP214 Eleanor Williams Publications for gene: NUP214 were set to 31178128
Intellectual disability v3.406 NUP214 Eleanor Williams Classified gene: NUP214 as Amber List (moderate evidence)
Intellectual disability v3.406 NUP214 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from Grey to Amber.

Several cases reported, but developmental delay not reported in some cases until after febrile events.
Intellectual disability v3.406 NUP214 Eleanor Williams Gene: nup214 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.405 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. ; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v3.405 NUP214 Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families. Family A have first-cousin parents of Palestinian descent. The proband exhibited minor developmental delay from infancy, presented with ataxia, mental retardation, and intractable epilepsy and died at 11 years. He suffered deterioration in association with febrile illnesses. His cousin presented at 5.5 months with partially reversible encephalopathy and developmental regression after a febrile illness. Family B were sisters born to non-consanguineous parents of Northern European (non-Finnish) descent. The older sister had nystagmus at 2 months and mild hypotonia, but she was otherwise meeting milestones appropriately . At 15 months of age, she developed a fever that led to a rapid neurological decline, seizures, and abnormal movements. The younger sister presented at 7 months with failure to thrive and hyponatremia but was meeting developmental milestones appropriately. By 24 months of age, she had motor and speech delay, ataxic gait, and occasional very mild head bobbing. In family A a homozygous NUP214 p.Arg38Cys variant segregated with the disease in available family members. In family B the sisters were found to be compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6).; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable).

PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls,

PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G.

PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls.
Intellectual disability v3.405 NUP214 Eleanor Williams Phenotypes for gene: NUP214 were changed from developmental delay; intellectual disability; epileptic encephalopathy; developmental regression; microcephaly to developmental delay; intellectual disability; epileptic encephalopathy; developmental regression; microcephaly; {Encephalopathy, acute, infection-induced, susceptibility to, 9}, 618426
Intellectual disability v3.404 NUP214 Eleanor Williams reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: None; Publications: 31178128; Phenotypes: {Encephalopathy, acute, infection-induced, susceptibility to, 9}, 618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.404 GPSM2 Eleanor Williams edited their review of gene: GPSM2: Changed rating: AMBER
Primary immunodeficiency or monogenic inflammatory bowel disease v2.205 USP18 Arina Puzriakova Phenotypes for gene: USP18 were changed from Pseudo-TORCH syndrome 2, 617397; Autoinflammatory Disorders; TORCH like syndrome to Pseudo-TORCH syndrome 2, 617397; Autoinflammatory Disorders
Intellectual disability v3.404 GPSM2 Eleanor Williams Classified gene: GPSM2 as Green List (high evidence)
Intellectual disability v3.404 GPSM2 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green just now, but as there are only 2 families out of 19 in which mild cognitive delay is seen then the recommendation would be to rate this gene amber. This gene should be reviewed at the next GMS update.
Intellectual disability v3.404 GPSM2 Eleanor Williams Gene: gpsm2 has been classified as Green List (High Evidence).
Intellectual disability v3.403 GPSM2 Eleanor Williams Tag for-review tag was added to gene: GPSM2.
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Classified gene: USP18 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update - seizures reported in all families described to date.
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Gene: usp18 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.403 GPSM2 Eleanor Williams Phenotypes for gene: GPSM2 were changed from DEAFNESS AUTOSOMAL RECESSIVE TYPE 82 to Chudley-McCullough syndrome, 604213
Intellectual disability v3.402 GPSM2 Eleanor Williams Publications for gene: GPSM2 were set to 22578326
Intellectual disability v3.401 GPSM2 Eleanor Williams changed review comment from: Associated with Chudley-McCullough syndrome604213 in OMIM

Summary: From 19 reported families, 3 individuals from 2 families showed cognitive delay.

PMID: 27180139 - Hemzeh et al 2016 - report two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. A homozygous mutation in GPSM2 was found in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). The 12 year old brother showed cognitive delay, noted by the inability to tell the time in minutes, or to follow complex commands. The 11 year old brother could speak in sentences but with poor articulation, and could not respond to complex commands.

PMID: 23494849 - Almomani et al 2013 - report three patients from two unrelated Dutch families with CMS were investigated in which the same c.1473delG variant observed in 4 of the Menonite families by Doherty et al was observed. All three patients had normal cognitive abilities.

PMID: 22578326 - Doherty et al 2012 - report on 5 Menonite, 1 European-American, 1 Dutch and 1 Mexican-American family in which probands had severe/profound hearing loss and ventriculomegaly (total of 12 affected individuals). They also look again at the patients reported with autosomal recessive nonsyndromic deafness (DFNB82) by Walsh et al 2010 (PMID: 20602914, 1 proband ina Pakistani family) and Yariz et al 2012 (PMID: 21348867, 3 probands in a Turkish family) who they found had brain abnormalities consistent with with a diagnosis of Chudley-McCullough syndrome.
Oout of the 16 patients reported, only one had developmental issues beyond what is typically seen in individuals with severe hearing loss.



- -; to: Associated with Chudley-McCullough syndrome604213 in OMIM

Summary: From 19 reported families, 3 individuals from 2 families showed cognitive delay.

PMID: 27180139 - Hemzeh et al 2016 - report two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. A homozygous mutation in GPSM2 was found in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). The 12 year old brother showed cognitive delay, noted by the inability to tell the time in minutes, or to follow complex commands. The 11 year old brother could speak in sentences but with poor articulation, and could not respond to complex commands. The poor articulation was thought to be due to late cochlear implant surgery.

PMID: 23494849 - Almomani et al 2013 - report three patients from two unrelated Dutch families with CMS were investigated in which the same c.1473delG variant observed in 4 of the Menonite families by Doherty et al was observed. All three patients had normal cognitive abilities.

PMID: 22578326 - Doherty et al 2012 - report on 5 Menonite, 1 European-American, 1 Dutch and 1 Mexican-American family in which probands had severe/profound hearing loss and ventriculomegaly (total of 12 affected individuals). They also look again at the patients reported with autosomal recessive nonsyndromic deafness (DFNB82) by Walsh et al 2010 (PMID: 20602914, 1 proband ina Pakistani family) and Yariz et al 2012 (PMID: 21348867, 3 probands in a Turkish family) who they found had brain abnormalities consistent with with a diagnosis of Chudley-McCullough syndrome.
Oout of the 16 patients reported, only one had developmental issues beyond what is typically seen in individuals with severe hearing loss.



- -
Early onset or syndromic epilepsy v2.163 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Early onset or syndromic epilepsy v2.163 USP18 Arina Puzriakova gene: USP18 was added
gene: USP18 was added to Genetic epilepsy syndromes. Sources: Literature
treatable, for-review tags were added to gene: USP18.
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to 12833411; 27325888; 31940699
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2, 617397
Review for gene: USP18 was set to GREEN
Added comment: - PMID: 27325888 (2016) - Three sibs from a consanguineous Turkish family with a homozygous variant (c.652C>T, p.Q218X) in USP18. Antenatal presentation in one sib led to termination of pregnancy at 22 wk of gestation, and in the remaining two children presentation was neonatal and resulted in death within 2 weeks of life. In the latter two individuals manifestations included severe intracerebral haemorrhages, liver dysfunction, ascites, and lactic acidosis. One sib additionally had severe thrombocytopenia with petechiae, while the other developed seizures.

Two German sibs, previously reported in PMID: 12833411 (2013), were found to be compound het for the same p.Q218X variant and a cryptic 3-prime deletion of the USP18 gene. They presented thrombocytopenia, petechiae, ascites, hepatomegaly, and systemic calcifications. Within the first days of life, they developed seizures and died from severe cerebral haemorrhage.

Haplotype analysis of the region containing the Q218X mutation suggested a common ancestor between the 2 families and a founder effect.

- PMID: 31940699 (2020) - One Saudi Arabian boy with a homozygous splice-site variant (c.1073+1G>A) in USP18, presented hydrocephalus with seizures, intraventricular haemorrhage, brain calcifications, necrotizing cellulitis, systemic inflammation, multiple organ failure, and respiratory failure. This was the only patient to survive beyond the perinatal period owing to supportive care and prompt treatment with ruxolitinib. At the time of publication, the child was 3-years-old and was in full remission of clinical manifestations while continuing to receive oral ruxolitinib. He continues to grow normally, however authors note delay in developmental milestones.
Sources: Literature
Intellectual disability v3.401 GPSM2 Eleanor Williams edited their review of gene: GPSM2: Changed publications: 27180139, 23494849, 22578326, 20602914, 21348867; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.401 GPSM2 Eleanor Williams commented on gene: GPSM2
White matter disorders and cerebral calcification - childhood onset v1.18 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
White matter disorders and cerebral calcification - childhood onset v1.18 USP18 Arina Puzriakova reviewed gene: USP18: Rating: GREEN; Mode of pathogenicity: None; Publications: 12833411, 27325888, 31940699; Phenotypes: Pseudo-TORCH syndrome 2, 617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.18 USP18 Arina Puzriakova Publications for gene: USP18 were set to PMID: 27325888
White matter disorders and cerebral calcification - childhood onset v1.17 USP18 Arina Puzriakova Phenotypes for gene: USP18 were changed from pseudo-TORCH syndrome to Pseudo-TORCH syndrome 2, 617397
White matter disorders and cerebral calcification - childhood onset v1.16 USP18 Arina Puzriakova Tag treatable tag was added to gene: USP18.
Intellectual disability v3.401 USP18 Arina Puzriakova Classified gene: USP18 as Red List (low evidence)
Intellectual disability v3.401 USP18 Arina Puzriakova Added comment: Comment on list classification: DD reported in one surviving patient. However, this only became apparent following treatment which was administered after genetic diagnosis was already achieved. DD is therefore unlikely represent the clinical indication to prompt testing in the neonatal period.

Therefore keeping rating Red on the ID panel. USP18 is Green on other relevant panels (White matter disorders and cerebral calcification, PID) which should be adequate for detecting these cases.
Intellectual disability v3.401 USP18 Arina Puzriakova Gene: usp18 has been classified as Red List (Low Evidence).
Intellectual disability v3.400 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Intellectual disability v3.400 FLVCR1 Eleanor Williams Tag for-review tag was added to gene: FLVCR1.
Intellectual disability v3.400 USP18 Arina Puzriakova Tag treatable tag was added to gene: USP18.
Intellectual disability v3.400 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Green List (high evidence)
Intellectual disability v3.400 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Leaving this gene green for now, but only one case where intellectual disability was reported. This gene should be updated at the next GMS review.
Intellectual disability v3.400 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Green List (High Evidence).
Intellectual disability v3.399 USP18 Arina Puzriakova Publications for gene: USP18 were set to
Intellectual disability v3.398 USP18 Arina Puzriakova Mode of inheritance for gene: USP18 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.397 FLVCR1 Eleanor Williams edited their review of gene: FLVCR1: Changed rating: RED; Changed publications: 30656474, 22279524, 21267618, 21070897, 9409377, 30444160; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.397 USP18 Arina Puzriakova reviewed gene: USP18: Rating: ; Mode of pathogenicity: None; Publications: 12833411, 27325888, 31940699; Phenotypes: Pseudo-TORCH syndrome 2, 617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.397 B9D1 Ivone Leong Classified gene: B9D1 as Amber List (moderate evidence)
Intellectual disability v3.397 B9D1 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber. Mild ID was only seen in 1 case.
Intellectual disability v3.397 B9D1 Ivone Leong Gene: b9d1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.396 MGP Sarah Leigh Publications for gene: MGP were set to 15810001; 9916809
Intellectual disability v3.395 HYLS1 Catherine Snow Tag for-review tag was added to gene: HYLS1.
Intellectual disability v3.395 HYLS1 Catherine Snow reviewed gene: HYLS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome, MIM#236680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.395 MGP Sarah Leigh Tag for-review tag was added to gene: MGP.
Intellectual disability v3.395 MGP Sarah Leigh reviewed gene: MGP: Rating: RED; Mode of pathogenicity: None; Publications: 24458983, 29928182, 25123378, 26349188, 26758921; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.395 B9D1 Ivone Leong Publications for gene: B9D1 were set to 24886560; 25920555
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Tag for-review tag was added to gene: MADD.
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Classified gene: MADD as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is enough evidence to support a gene-disease association. The gene has been given an Amber rating and will be promoted to Green at the next review.
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Gene: madd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.394 FLVCR1 Eleanor Williams commented on gene: FLVCR1
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Classified gene: DLL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Added comment: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Gene: dll1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.160 DLL1 Catherine Snow reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, 618709; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.394 MGP Sarah Leigh Phenotypes for gene: MGP were changed from KEUTEL SYNDROME to Keutel syndrome 245150
Intellectual disability v3.393 MADD Ivone Leong Tag for-review tag was added to gene: MADD.
Intellectual disability v3.393 LGI4 Sarah Leigh reviewed gene: LGI4: Rating: RED; Mode of pathogenicity: None; Publications: 28318499; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.393 MADD Ivone Leong Classified gene: MADD as Amber List (moderate evidence)
Intellectual disability v3.393 MADD Ivone Leong Added comment: Comment on list classification: Based on expert review provided by Konstantinos Varvagiannis and Zornitza Stark, there is enough evidence to support a gene-disease association. This gene has been promoted from Red to Amber and will be promoted to Green status at next panel review.
Intellectual disability v3.393 MADD Ivone Leong Gene: madd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.392 MADD Ivone Leong Publications for gene: MADD were set to
Fetal anomalies v1.101 TMEM260 Rhiannon Mellis reviewed gene: TMEM260: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28318500; Phenotypes: STructural heart defects, Renal anomalies, Agenesis of corpus callosum; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.391 MADD Ivone Leong Phenotypes for gene: MADD were changed from to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004
Early onset or syndromic epilepsy v2.160 MADD Ivone Leong Phenotypes for gene: MADD were changed from Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004
Intellectual disability v3.390 USP18 Arina Puzriakova Phenotypes for gene: USP18 were changed from to Pseudo-TORCH syndrome 2, 617397
Intellectual disability v3.389 DLL1 Catherine Snow Publications for gene: DLL1 were set to 31353024
Intellectual disability v3.388 LGI4 Sarah Leigh Tag for-review tag was added to gene: LGI4.
Intellectual disability v3.388 DLL1 Catherine Snow Classified gene: DLL1 as Amber List (moderate evidence)
Intellectual disability v3.388 DLL1 Catherine Snow Added comment: Comment on list classification: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.
Intellectual disability v3.388 DLL1 Catherine Snow Gene: dll1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.387 DLL1 Catherine Snow Tag for-review tag was added to gene: DLL1.
Intellectual disability v3.387 DLL1 Catherine Snow edited their review of gene: DLL1: Changed rating: GREEN
Intellectual disability v3.387 DLL1 Catherine Snow reviewed gene: DLL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31353024, 31602192; Phenotypes: Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures 618709; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.387 TBR1 Ivone Leong Publications for gene: TBR1 were set to 23160955
Intellectual disability v3.386 TBR1 Ivone Leong Phenotypes for gene: TBR1 were changed from AUTISM to Autism; Intellectual developmental disorder with autism and speech delay, 606053; Abnormal cortical gyration
Intellectual disability v3.385 RHEB Arina Puzriakova Classified gene: RHEB as Amber List (moderate evidence)
Intellectual disability v3.385 RHEB Arina Puzriakova Added comment: Comment on list classification: Three individuals from two unrelated families reported in PMID:29051493 with severe-profound ID - sufficient evidence to rate this gene Amber (previously erroneously demoted to Red).
Intellectual disability v3.385 RHEB Arina Puzriakova Gene: rheb has been classified as Amber List (Moderate Evidence).
RASopathies v1.73 SHOC2 Ivone Leong Phenotypes for gene: SHOC2 were changed from Noonan-like syndrome with loose anagen hair to Noonan syndrome-like with loose anagen hair 1, 607721
RASopathies v1.72 RRAS2 Ivone Leong Publications for gene: RRAS2 were set to 31130282
RASopathies v1.71 RRAS2 Ivone Leong Phenotypes for gene: RRAS2 were changed from Noonan syndrome 12, OMIM #618624 to Noonan syndrome 12, 618624
RASopathies v1.70 NRAS Ivone Leong Phenotypes for gene: NRAS were changed from Noonan syndrome 6 613224; Cardio-Facio-cutanenous syndrome; CFC Syndrome to Noonan syndrome 6 613224; Cardio-Facio-cutanenous syndrome
RASopathies v1.69 MRAS Ivone Leong Publications for gene: MRAS were set to 28289718
RASopathies v1.68 MRAS Ivone Leong Phenotypes for gene: MRAS were changed from Noonan syndrome to Noonan syndrome 11, 618499
RASopathies v1.67 MAP2K1 Ivone Leong Phenotypes for gene: MAP2K1 were changed from Cardiofaciocutaneous syndrome 3; Cardiofaciocutaneous Syndrome; Cardio-Facio-Cutaneous syndrome; CFC syndrome; LEOPARD syndrome; ?Noonan syndrome to Cardiofaciocutaneous syndrome 3, 615279; LEOPARD syndrome; ?Noonan syndrome
RASopathies v1.66 MAP2K1 Ivone Leong Added comment: Comment on publications: PMID: 23321623 (publication referring to Noonan syndrome association).
RASopathies v1.66 MAP2K1 Ivone Leong Publications for gene: MAP2K1 were set to 21396583; 23321623 (publication referring to Noonan syndrome association).
RASopathies v1.65 MAP2K1 Ivone Leong Publications for gene: MAP2K1 were set to PMID: 21396583; 23321623 (publication referring to Noonan syndrome association).
RASopathies v1.64 LZTR1 Ivone Leong Phenotypes for gene: LZTR1 were changed from Noonan syndrome 10 616564; Schwannomatosis-2, susceptibility to 615670 to Noonan syndrome 10 616564; Schwannomatosis-2, susceptibility to 615670; Noonan syndrome 2, 605275
RASopathies v1.63 HRAS Ivone Leong Phenotypes for gene: HRAS were changed from Costello syndrome to Costello syndrome, 218040
Hereditary spastic paraplegia, childhood onset v2.19 Arina Puzriakova Panel version has been signed off
Hereditary spastic paraplegia, adult onset v1.12 ATXN10_ATTCT Arina Puzriakova Tag for-review tag was added to STR: ATXN10_ATTCT.
Neurodegenerative disorders, adult onset v2.32 Arina Puzriakova Panel version has been signed off
Neurodegenerative disorders, adult onset v2.30 PPP2R2B_CAG Arina Puzriakova Classified STR: PPP2R2B_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.30 PPP2R2B_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.30 PPP2R2B_CAG Arina Puzriakova Str: ppp2r2b_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.29 PPP2R2B_CAG Arina Puzriakova Tag for-review tag was added to STR: PPP2R2B_CAG.
Neurodegenerative disorders, adult onset v2.29 NOP56_GGCCTG Arina Puzriakova Classified STR: NOP56_GGCCTG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.29 NOP56_GGCCTG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.29 NOP56_GGCCTG Arina Puzriakova Str: nop56_ggcctg has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.28 NOP56_GGCCTG Arina Puzriakova Tag for-review tag was added to STR: NOP56_GGCCTG.
Neurodegenerative disorders, adult onset v2.28 FXN_GAA Arina Puzriakova Classified STR: FXN_GAA as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.28 FXN_GAA Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.28 FXN_GAA Arina Puzriakova Str: fxn_gaa has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.27 FXN_GAA Arina Puzriakova Tag for-review tag was added to STR: FXN_GAA.
Neurodegenerative disorders, adult onset v2.27 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.27 CSTB_CCCCGCCCCGCG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.27 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.26 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag for-review tag was added to STR: CSTB_CCCCGCCCCGCG.
Neurodegenerative disorders, adult onset v2.26 CACNA1A_CAG Arina Puzriakova Classified STR: CACNA1A_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.26 CACNA1A_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.26 CACNA1A_CAG Arina Puzriakova Str: cacna1a_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.25 CACNA1A_CAG Arina Puzriakova Tag for-review tag was added to STR: CACNA1A_CAG.
Neurodegenerative disorders, adult onset v2.25 ATXN7_CAG Arina Puzriakova Classified STR: ATXN7_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.25 ATXN7_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.25 ATXN7_CAG Arina Puzriakova Str: atxn7_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.24 ATXN7_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN7_CAG.
Neurodegenerative disorders, adult onset v2.24 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.24 ATXN3_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.24 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.23 ATXN3_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN3_CAG.
Neurodegenerative disorders, adult onset v2.23 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.23 ATXN2_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.23 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.22 ATXN2_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN2_CAG.
Neurodegenerative disorders, adult onset v2.22 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.22 ATXN1_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.22 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.21 ATXN1_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN1_CAG.
Neurodegenerative disorders, adult onset v2.21 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.21 ATXN10_ATTCT Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Neurodegenerative disorders, adult onset v2.21 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.20 ATXN10_ATTCT Arina Puzriakova Tag for-review tag was added to STR: ATXN10_ATTCT.
Dystonia, chorea or related movement disorder, adult onset v1.14 PPP2R2B_CAG Arina Puzriakova Tag for-review tag was added to STR: PPP2R2B_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.14 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag for-review tag was added to STR: CSTB_CCCCGCCCCGCG.
Dystonia, chorea or related movement disorder, adult onset v1.14 CACNA1A_CAG Arina Puzriakova Tag for-review tag was added to STR: CACNA1A_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.14 ATXN3_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN3_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.14 ATXN2_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN2_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.14 ATXN1_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN1_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.24 Arina Puzriakova Panel version has been signed off
Ataxia and cerebellar anomalies - childhood onset v2.22 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.22 ATXN3_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.22 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.21 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.21 TBP_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.21 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.20 TBP_CAG Arina Puzriakova Tag for-review tag was added to STR: TBP_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.20 PPP2R2B_CAG Arina Puzriakova Classified STR: PPP2R2B_CAG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.20 PPP2R2B_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.20 PPP2R2B_CAG Arina Puzriakova Str: ppp2r2b_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.19 PPP2R2B_CAG Arina Puzriakova Tag for-review tag was added to STR: PPP2R2B_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.19 NOP56_GGCCTG Arina Puzriakova Classified STR: NOP56_GGCCTG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.19 NOP56_GGCCTG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.19 NOP56_GGCCTG Arina Puzriakova Str: nop56_ggcctg has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.18 NOP56_GGCCTG Arina Puzriakova Tag for-review tag was added to STR: NOP56_GGCCTG.
Ataxia and cerebellar anomalies - childhood onset v2.18 CACNA1A_CAG Arina Puzriakova Classified STR: CACNA1A_CAG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.18 CACNA1A_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.18 CACNA1A_CAG Arina Puzriakova Str: cacna1a_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.17 CACNA1A_CAG Arina Puzriakova Tag for-review tag was added to STR: CACNA1A_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.17 ATXN3_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN3_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.17 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.17 ATXN1_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.17 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.16 ATXN1_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN1_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.16 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.16 ATXN10_ATTCT Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group
Ataxia and cerebellar anomalies - childhood onset v2.16 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.15 ATXN10_ATTCT Arina Puzriakova Tag for-review tag was added to STR: ATXN10_ATTCT.
Ataxia and cerebellar anomalies - childhood onset v2.15 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.15 ATN1_CAG Arina Puzriakova Added comment: Comment on list classification: Downgraded from Green to Amber as this STR was not listed on the recent GMS STRs document supplied by Jane Deller (NHS England) on behalf of GLHs for the GMS Neurology Test Group.
Ataxia and cerebellar anomalies - childhood onset v2.15 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.14 ATN1_CAG Arina Puzriakova Tag for-review tag was added to STR: ATN1_CAG.
Rhabdomyolysis and metabolic muscle disorders v1.42 TYMP Zornitza Stark reviewed gene: TYMP: Rating: RED; Mode of pathogenicity: None; Publications: 24199812; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type) MIM#603041; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.42 TSFM Zornitza Stark reviewed gene: TSFM: Rating: RED; Mode of pathogenicity: None; Publications: 31267352, 17033963; Phenotypes: Combined oxidative phosphorylation deficiency 3 MIM#610505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.42 TSEN54 Zornitza Stark reviewed gene: TSEN54: Rating: RED; Mode of pathogenicity: None; Publications: 23177318; Phenotypes: Pontocerebellar hypoplasia type 2A MIM#277470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.42 SGCA Zornitza Stark gene: SGCA was added
gene: SGCA was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list
Mode of inheritance for gene: SGCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGCA were set to 27297959; 26453141; 23989969
Phenotypes for gene: SGCA were set to Muscular dystrophy, limb-girdle, autosomal recessive 3 MIM#608099
Review for gene: SGCA was set to GREEN
gene: SGCA was marked as current diagnostic
Added comment: Four unrelated cases reported with rhabdomyolysis or exercise intolerance.
Sources: Expert list
Rhabdomyolysis and metabolic muscle disorders v1.42 SCN4A Zornitza Stark gene: SCN4A was added
gene: SCN4A was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list
Mode of inheritance for gene: SCN4A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SCN4A were set to 23801527; 28779239; 32978841
Phenotypes for gene: SCN4A were set to SCN4A-related muscle disorders
Review for gene: SCN4A was set to GREEN
gene: SCN4A was marked as current diagnostic
Added comment: SCN4A variants are associated with a number of disorders disorders of abnormal skeletal muscle relaxation and contraction and rhabdomyolysis is specifically reported.
Sources: Expert list
Rhabdomyolysis and metabolic muscle disorders v1.42 PRKAG2 Zornitza Stark reviewed gene: PRKAG2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, hypertrophic 6 600858, Glycogen storage disease of heart, lethal congenital 261740, Wolff-Parkinson-White syndrome 194200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.42 PHKB Zornitza Stark reviewed gene: PHKB: Rating: RED; Mode of pathogenicity: None; Publications: 9215682, 30397902; Phenotypes: Phosphorylase kinase deficiency of liver and muscle, autosomal recessive MIM#261750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.42 GMPPB Zornitza Stark gene: GMPPB was added
gene: GMPPB was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list
Mode of inheritance for gene: GMPPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GMPPB were set to 28456886; 27874200; 25681410
Phenotypes for gene: GMPPB were set to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 MIM#615352; Limb myalgia; exercise intolerance; myoglobinuria
Review for gene: GMPPB was set to GREEN
gene: GMPPB was marked as current diagnostic
Added comment: Three unrelated cases reported with rhabdomyolysis in the context of this muscle disorder.
Sources: Expert list
Rhabdomyolysis and metabolic muscle disorders v1.42 FKTN Zornitza Stark reviewed gene: FKTN: Rating: RED; Mode of pathogenicity: None; Publications: 25929793; Phenotypes: ; Mode of inheritance: None
Rhabdomyolysis and metabolic muscle disorders v1.42 FDX2 Zornitza Stark gene: FDX2 was added
gene: FDX2 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list
Mode of inheritance for gene: FDX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDX2 were set to 24281368; 30010796; 28803783
Phenotypes for gene: FDX2 were set to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy MIM#251900
Review for gene: FDX2 was set to GREEN
Added comment: Three unrelated cases reported with rhabdomyolysis/myoglobinuria.
Sources: Expert list
Retinal disorders v2.17 ROM1 Zornitza Stark reviewed gene: ROM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32036094, 8202715, 30630813, 24618324, 20300562, 32716032; Phenotypes: Retinitis pigmentosa 7, digenic form, MIM# 608133; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Monogenic hearing loss v2.94 COL2A1 Eleanor Williams Tag for-review tag was added to gene: COL2A1.
Monogenic hearing loss v2.94 COL2A1 Eleanor Williams changed review comment from: Comment on list classification: Upgrading from red to amber. Should be reviewed by the GMS as to whether it is appropriate to make green.; to: Comment on list classification: Upgrading from red to amber. Should be reviewed by the GMS as to whether it is appropriate to make green. Hearing loss is less predominant in individuals with variants in this gene than in some other Stickler syndrome genes, however if hearing loss is picked up and Stickler syndrome is identified early then eye related symptoms may be treatable.
Monogenic hearing loss v2.94 COL2A1 Eleanor Williams edited their review of gene: COL2A1: Changed rating: GREEN
Fetal anomalies v1.101 CTNND1 Eleanor Williams Tag for-review tag was added to gene: CTNND1.
Fetal anomalies v1.101 CTNND1 Eleanor Williams Classified gene: CTNND1 as Amber List (moderate evidence)
Fetal anomalies v1.101 CTNND1 Eleanor Williams Added comment: Comment on list classification: Leaving amber for now, but this gene should be reviewed at the next GMS update.
Fetal anomalies v1.101 CTNND1 Eleanor Williams Gene: ctnnd1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.100 CTNND1 Eleanor Williams reviewed gene: CTNND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32196547; Phenotypes: Blepharocheilodontic syndrome 2, 617681, cardiovascular anomalies, developmental delay, choanal atresia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Choanal atresia v1.15 CTNND1 Eleanor Williams Classified gene: CTNND1 as Green List (high evidence)
Choanal atresia v1.15 CTNND1 Eleanor Williams Added comment: Comment on list classification: Rating this gene green. Choanal atresia has been observed in 3 families with variants in this gene.
Choanal atresia v1.15 CTNND1 Eleanor Williams Gene: ctnnd1 has been classified as Green List (High Evidence).
Choanal atresia v1.14 CTNND1 Eleanor Williams gene: CTNND1 was added
gene: CTNND1 was added to Choanal atresia. Sources: Literature
Mode of inheritance for gene: CTNND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNND1 were set to 32196547
Phenotypes for gene: CTNND1 were set to chonal atresia
Added comment: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13). Chonal atresia was seen in 4 individuals from 3 families
Sources: Literature
Familial non syndromic congenital heart disease v1.53 CTNND1 Eleanor Williams Classified gene: CTNND1 as Green List (high evidence)
Familial non syndromic congenital heart disease v1.53 CTNND1 Eleanor Williams Added comment: Comment on list classification: Rating this gene green, after consultation with Genomics England clinician, as variants in this gene associated with cardiovascular anomalies in 5 families.
Familial non syndromic congenital heart disease v1.53 CTNND1 Eleanor Williams Gene: ctnnd1 has been classified as Green List (High Evidence).
Familial non syndromic congenital heart disease v1.52 CTNND1 Eleanor Williams gene: CTNND1 was added
gene: CTNND1 was added to Familial non syndromic congenital heart disease. Sources: Literature
Mode of inheritance for gene: CTNND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNND1 were set to 32196547
Phenotypes for gene: CTNND1 were set to cardiovascular anomalies
Review for gene: CTNND1 was set to GREEN
Added comment: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).
The cardiovasuclar anomalies were seen in 6 individuals from 5 different families.
Sources: Literature
Intellectual disability v3.384 CTNND1 Eleanor Williams Classified gene: CTNND1 as Amber List (moderate evidence)
Intellectual disability v3.384 CTNND1 Eleanor Williams Added comment: Comment on list classification: Rating as amber but could potentially be green. Individuals from 5/9 families have reported developmental delay/learning difficulty. This gene should be reviewed at the next GMS update.
Intellectual disability v3.384 CTNND1 Eleanor Williams Gene: ctnnd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.383 CTNND1 Eleanor Williams Tag for-review tag was added to gene: CTNND1.
Intellectual disability v3.383 CTNND1 Eleanor Williams Phenotypes for gene: CTNND1 were changed from to developmental delay
Intellectual disability v3.382 CTNND1 Eleanor Williams gene: CTNND1 was added
gene: CTNND1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTNND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNND1 were set to 32196547
Review for gene: CTNND1 was set to GREEN
Added comment: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13)
Sources: Literature
Clefting v2.4 CTNND1 Eleanor Williams Publications for gene: CTNND1 were set to 28301459
Fetal anomalies v1.100 TRPM7 Eleanor Williams Classified gene: TRPM7 as Amber List (moderate evidence)
Fetal anomalies v1.100 TRPM7 Eleanor Williams Added comment: Comment on list classification: Adding this gene as amber. This gene should be reviewed for relevance on phenotypic grounds
Fetal anomalies v1.100 TRPM7 Eleanor Williams Gene: trpm7 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.99 TRPM7 Eleanor Williams reviewed gene: TRPM7: Rating: AMBER; Mode of pathogenicity: None; Publications: 32503408, 31423533; Phenotypes: Cardiac arrhythmia, stillbirth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ectodermal dysplasia v1.10 C3orf52 Eleanor Williams Tag for-review tag was added to gene: C3orf52.
Ectodermal dysplasia v1.10 C3orf52 Eleanor Williams Classified gene: C3orf52 as Amber List (moderate evidence)
Ectodermal dysplasia v1.10 C3orf52 Eleanor Williams Added comment: Comment on list classification: Adding this gene as Amber as two cases reported. This gene should be looked at, at the next GMS review to assess whether the phenotype is relevant to the panel.
Ectodermal dysplasia v1.10 C3orf52 Eleanor Williams Gene: c3orf52 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.9 C3orf52 Eleanor Williams gene: C3orf52 was added
gene: C3orf52 was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: C3orf52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C3orf52 were set to 32336749
Phenotypes for gene: C3orf52 were set to Localized hypotrichosis
Review for gene: C3orf52 was set to AMBER
Added comment: Not associated with a phenotype in OMIM.

PMID: 32336749 - Malki et al 2020 - identified homozygous variants in C3ORF52 in four individuals with Localized autosomal recessive hypotrichosis (LAH) (2 families). C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H-mediated LPA biosynthesis. Abstract only accessed.
Sources: Literature
Non-syndromic hypotrichosis v1.4 C3orf52 Eleanor Williams Classified gene: C3orf52 as Amber List (moderate evidence)
Non-syndromic hypotrichosis v1.4 C3orf52 Eleanor Williams Added comment: Comment on list classification: 2 cases, but may not be relevant to the panel (localized hypotrichosis)
Non-syndromic hypotrichosis v1.4 C3orf52 Eleanor Williams Gene: c3orf52 has been classified as Amber List (Moderate Evidence).
Non-syndromic hypotrichosis v1.3 C3orf52 Eleanor Williams gene: C3orf52 was added
gene: C3orf52 was added to Non-syndromic hypotrichosis. Sources: Literature
Mode of inheritance for gene: C3orf52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C3orf52 were set to 32336749
Phenotypes for gene: C3orf52 were set to Localized hypotrichosis
Review for gene: C3orf52 was set to AMBER
Added comment: PMID: 32336749 - Malki et al 2020 - identified homozygous variants in C3ORF52 in four individuals with Localized autosomal recessive hypotrichosis (LAH) (2 families). C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H-mediated LPA biosynthesis. Abstract only accessed.

Although localized hypotrichosis is an exclusion criteria for this gene, it has been added to this panel as Amber as maybe useful information in the future.
Sources: Literature
Kleine-Levin syndrome v1.7 CRY1 Eleanor Williams Classified gene: CRY1 as Red List (low evidence)
Kleine-Levin syndrome v1.7 CRY1 Eleanor Williams Added comment: Comment on list classification: Adding this gene as red to the panel after consultation with the Genomics England clinical team. There are sufficient cases to rate higher, but the phenotype, although sleep related, is not relevant to the panel scope which targets hypersomnolence, so keeping red for now.
Kleine-Levin syndrome v1.7 CRY1 Eleanor Williams Gene: cry1 has been classified as Red List (Low Evidence).
Kleine-Levin syndrome v1.6 CRY1 Eleanor Williams gene: CRY1 was added
gene: CRY1 was added to Kleine-Levin syndrome. Sources: Literature
Mode of inheritance for gene: CRY1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CRY1 were set to 32538895; 28388406
Phenotypes for gene: CRY1 were set to Attention deficit/hyperactivity disorder (ADHD); Delayed sleep phase disorder (DSPD)
Review for gene: CRY1 was set to RED
Added comment: Reviewed by Ee Ming Wong (Victorian Clinical Genetics Services) in PanelApp Australia https://panelapp.agha.umccr.org/panels/137/gene/CRY1/.

PMID: 32538895 - Onat et al 2020- heterozygous variants in 15 families with ADHD/insomnia. 
PMID: 28388406 - Patke et al 2017 - identify the CRY1 Δ11 GOF allele in an initial family and then additional families with Delayed Sleep Phase Disorder.
Sources: Literature
RASopathies v1.62 RREB1 Arina Puzriakova Classified gene: RREB1 as Red List (low evidence)
RASopathies v1.62 RREB1 Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently only a single individuals reported (PMID:32938917) with clinical features consistent with a Noonan-spectrum disorder and a 6p-interstitial microdeletion which encompassed 11 genes, including RREB1. Additional cases would help delineate the relevance of the RREB1 gene to the observed phenotype.
RASopathies v1.62 RREB1 Arina Puzriakova Gene: rreb1 has been classified as Red List (Low Evidence).
Cholestasis v1.36 UNC45A Ivone Leong Classified gene: UNC45A as Amber List (moderate evidence)
Cholestasis v1.36 UNC45A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and will be promoted to Green at the next panel review.
Cholestasis v1.36 UNC45A Ivone Leong Gene: unc45a has been classified as Amber List (Moderate Evidence).
Cholestasis v1.35 UNC45A Ivone Leong Tag for-review tag was added to gene: UNC45A.
Cholestasis v1.35 KIF12 Ivone Leong Tag for-review tag was added to gene: KIF12.
Cholestasis v1.35 KIF12 Ivone Leong Classified gene: KIF12 as Amber List (moderate evidence)
Cholestasis v1.35 KIF12 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. This gene has been given an Amber status and will be promoted to Green at the next review.
Cholestasis v1.35 KIF12 Ivone Leong Gene: kif12 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.34 LSR Ivone Leong Tag watchlist tag was added to gene: LSR.
Cholestasis v1.34 LSR Ivone Leong Classified gene: LSR as Amber List (moderate evidence)
Cholestasis v1.34 LSR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. As there are only 2 cases this gene has been given an Amber rating.
Cholestasis v1.34 LSR Ivone Leong Gene: lsr has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.204 RELN Eleanor Williams gene: RELN was added
gene: RELN was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RELN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RELN were set to 32001840
Phenotypes for gene: RELN were set to Ankylosing spondylitis
Review for gene: RELN was set to RED
Added comment: PMID: 32001840 - Garshasbi et al 2020. Report a large consanguineous Iranian family with ankylosing spondylitis and a heterozygous variant in RELN.

After consultation with the Genomics England clinical team it was decided to add this gene to the PID panel with a red rating until the phenotype association is confirmed. In general there is local spinal inflammation, rather than a systemic inflammatory response.
Sources: Literature
Intellectual disability v3.381 WDR83OS Ivone Leong gene: WDR83OS was added
gene: WDR83OS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to 30250217
Phenotypes for gene: WDR83OS were set to Intellectual disability
Review for gene: WDR83OS was set to RED
Added comment: One consanguineous family with three affected individuals with homozygous split site variant in this gene. All three have ID.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.203 STAT4 Arina Puzriakova Phenotypes for gene: STAT4 were changed from {Systemic lupus erythematosus, susceptibility to, 11}, 612253 to Paracoccidioidomycosis; Impaired IFN-γ Immunity; {Systemic lupus erythematosus, susceptibility to, 11}, 612253
Primary immunodeficiency or monogenic inflammatory bowel disease v2.202 STAT4 Arina Puzriakova Publications for gene: STAT4 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.201 STAT4 Arina Puzriakova Mode of inheritance for gene: STAT4 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.200 STAT4 Arina Puzriakova Classified gene: STAT4 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.200 STAT4 Arina Puzriakova Added comment: Comment on list classification: Only one kindred reported with a heterozygous variant in STAT4 associated with susceptibility to paracoccidioidomycosis. Additional cases needed to validate pathogenicity and therefore keeping rating Red.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.200 STAT4 Arina Puzriakova Gene: stat4 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.199 STAT4 Arina Puzriakova reviewed gene: STAT4: Rating: ; Mode of pathogenicity: None; Publications: 29029192; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cholestasis v1.33 WDR83OS Ivone Leong Classified gene: WDR83OS as Red List (low evidence)
Cholestasis v1.33 WDR83OS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene has been given a Red rating as there is only one case available.
Cholestasis v1.33 WDR83OS Ivone Leong Gene: wdr83os has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v2.17 GALM Ivone Leong Tag watchlist tag was added to gene: GALM.
Bilateral congenital or childhood onset cataracts v2.17 GALM Ivone Leong Classified gene: GALM as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.17 GALM Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Based on the available evidence there is currently not enough evidence to support a gene-disease assocation; therefore, this gene has been given an Amber rating.
Bilateral congenital or childhood onset cataracts v2.17 GALM Ivone Leong Gene: galm has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.16 GALM Ivone Leong Phenotypes for gene: GALM were changed from type IV galactosaemia to Galactosemia IV, 618881
Bleeding and platelet disorders v1.12 BLOC1S5 Arina Puzriakova Classified gene: BLOC1S5 as Amber List (moderate evidence)
Bleeding and platelet disorders v1.12 BLOC1S5 Arina Puzriakova Added comment: Comment on list classification: Two unrelated patients with this mild form of HPS. Rating Amber awaiting further publications with additional cases or clinical evidence supporting this gene-disease association.
Bleeding and platelet disorders v1.12 BLOC1S5 Arina Puzriakova Gene: bloc1s5 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.11 BLOC1S5 Arina Puzriakova reviewed gene: BLOC1S5: Rating: ; Mode of pathogenicity: None; Publications: 32565547; Phenotypes: Hermansky–Pudlak syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.11 BLOC1S3 Arina Puzriakova Phenotypes for gene: BLOC1S3 were changed from 614077 Hermansky-Pudlak syndrome 8 to Hermansky-Pudlak syndrome 8, 614077
Bleeding and platelet disorders v1.10 BLOC1S3 Arina Puzriakova Added comment: Comment on publications: Added publication to support this gene-disease association.
Bleeding and platelet disorders v1.10 BLOC1S3 Arina Puzriakova Publications for gene: BLOC1S3 were set to 16385460; 22709368
Hereditary spastic paraplegia, childhood onset v2.17 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as No list
Hereditary spastic paraplegia, childhood onset v2.17 HTT_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been removed at the request of GHLs for the GMS Neurology Specialist Test Group as it is available as a core test for R68 Huntington Disease. Inclusion on panels for other neurological CIs raises concerns regarding counselling, and so it has been agreed that HTT_CAG will be excluded from this panel.
Hereditary spastic paraplegia, childhood onset v2.17 HTT_CAG Arina Puzriakova Str: htt_cag has been removed from the panel.
Cholestasis v1.32 GALM Ivone Leong Phenotypes for gene: GALM were changed from type IV galactosaemia to Galactosemia IV, 618881
Skeletal dysplasia v2.21 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to 27193493
Skeletal dysplasia v2.20 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Structural eye disease v1.12 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to 12036988; 17210863; 9620769; 10713890; 11007653; 12614756
Structural eye disease v1.11 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Anophthalmia or microphthalmia v1.29 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to
Anophthalmia or microphthalmia v1.28 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.99 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to
Fetal anomalies v1.98 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Sporadic aniridia v2.5 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to 19279310; 25691405; 27124303
Sporadic aniridia v2.4 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Familial cerebral small vessel disease v1.10 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to 22678982; 22903608; 25250569; 16551997; 23686687
Familial cerebral small vessel disease v1.9 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Glaucoma (developmental) v1.9 FOXC1 Eleanor Williams Publications for gene: FOXC1 were set to 9620769; 12614756; 10713890; 11007653; 12036988; 17210863
Glaucoma (developmental) v1.8 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.62 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.62 YIF1B Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next major review.

Profound delay in motor development is part of the phenotype, as well as dystonia, spasticity and dyskinesia.
Dystonia, chorea or related movement disorder, childhood onset v1.62 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.61 YIF1B Arina Puzriakova gene: YIF1B was added
gene: YIF1B was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
for-review tags were added to gene: YIF1B.
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Review for gene: YIF1B was set to GREEN
Added comment: - PMID: 32006098 - 6 individuals (from 5 families) with biallelic YIF1B truncating variants. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder including dystonia (5/6), spasticity (6/6), dyskinesia (5/5). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

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

Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichment in genes important for nervous system development and function.
Sources: Expert list
Cholestasis v1.31 PEX14 Ivone Leong Classified gene: PEX14 as Amber List (moderate evidence)
Cholestasis v1.31 PEX14 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is currently not enough evidence to support gene-disease association. This gene has been given Amber status until further evidence is available.
Cholestasis v1.31 PEX14 Ivone Leong Gene: pex14 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.98 NEK9 Rhiannon Mellis reviewed gene: NEK9: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26908619, 26633546; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.14 NEK9 Rhiannon Mellis reviewed gene: NEK9: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26908619; Phenotypes: Lethal congenital contracture syndrome 10; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.27 YIF1B Arina Puzriakova Tag for-review was removed from gene: YIF1B.
Tag watchlist tag was added to gene: YIF1B.
Severe microcephaly v2.27 YIF1B Arina Puzriakova Tag for-review tag was added to gene: YIF1B.
Severe microcephaly v2.27 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Severe microcephaly v2.27 YIF1B Arina Puzriakova Added comment: Comment on list classification: Although 5/6 individuals described in PMID:32006098 had microcephaly, 4 of these share the same founder variant and the severity of microcephaly is not specified. Therefore, rating Amber until further cases are reported (added to watchlist).
Severe microcephaly v2.27 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Added comment: Comment on list classification: Seizures reported in only 2 unrelated individuals (PMID:32006098). Rating Amber in anticipation of further publications/clinical evidence to support this association.
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Clefting v2.3 HYAL2 Aleš Maver changed review comment from: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP) in PMID:28081210. Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense variants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature; to: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP) in PMID:28081210. Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense variants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature
Cholestasis v1.30 PEX14 Ivone Leong Publications for gene: PEX14 were set to 21686775; 18285423
Intellectual disability v3.380 YIF1B Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.; to: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

- PMID: 32006098: GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Clefting v2.3 HYAL2 Aleš Maver changed review comment from: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP) in PMID:28081210. Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense vairants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature; to: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP) in PMID:28081210. Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense variants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature
Clefting v2.3 HYAL2 Aleš Maver changed review comment from: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP). Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense vairants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature; to: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP) in PMID:28081210. Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense vairants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature
Intellectual disability v3.380 YIF1B Arina Puzriakova changed review comment from: Comment on list classification: There are a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.; to: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Rare multisystem ciliopathy disorders v1.129 TBC1D32 Rhiannon Mellis reviewed gene: TBC1D32: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32573025, 31130284, 32060556; Phenotypes: OFD IX; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.380 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Intellectual disability v3.380 YIF1B Arina Puzriakova Added comment: Comment on list classification: There are a sufficient number of cases to rate this gene Green at the next GMS panel update.

GDD was reported in all 6 patients (5 families). At ages 4-11yrs, the best achieved social and language skills were limited to sounds in 4 individuals, and partial babbling or vocalisation in the remaining two, respectively.
Intellectual disability v3.380 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Clefting v2.3 HYAL2 Aleš Maver gene: HYAL2 was added
gene: HYAL2 was added to Clefting. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 28081210
Phenotypes for gene: HYAL2 were set to Cleft lip and palate, cor triatriatum
Penetrance for gene: HYAL2 were set to unknown
Review for gene: HYAL2 was set to RED
Added comment: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP). Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense vairants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: Literature
Intellectual disability v3.379 YIF1B Arina Puzriakova Tag for-review tag was added to gene: YIF1B.
Cholestasis v1.29 PEX14 Ivone Leong Phenotypes for gene: PEX14 were changed from Peroxisome biogenesis disorder 13A (Zellweger), MIM# 614887 to Peroxisome biogenesis disorder 13A (Zellweger), 614887
Cholestasis v1.28 PPM1F Ivone Leong Classified gene: PPM1F as Red List (low evidence)
Cholestasis v1.28 PPM1F Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. As there is currently only 1 case, this gene has been given a Red rating.
Cholestasis v1.28 PPM1F Ivone Leong Gene: ppm1f has been classified as Red List (Low Evidence).
Cholestasis v1.27 USP53 Ivone Leong commented on gene: USP53: There is enough evidence to support a gene-disease association. This gene will be promoted to Green status at the next review.
Cholestasis v1.27 USP53 Ivone Leong Tag for-review tag was added to gene: USP53.
Cholestasis v1.27 USP53 Ivone Leong Publications for gene: USP53 were set to 30250217; 32124521
Retinal disorders v2.17 PRPH2 Eleanor Williams commented on gene: PRPH2
Retinal disorders v2.17 ROM1 Eleanor Williams Publications for gene: ROM1 were set to
Cholestasis v1.26 USP53 Ivone Leong Phenotypes for gene: USP53 were changed from Paediatric cholestatic liver disease to Paediatric cholestatic liver disease; Cholestasis; deafness
Retinal disorders v2.16 ROM1 Eleanor Williams changed review comment from: PMID: 32716032 - Strayve et al 2020 - created mouse models to look at the effects of eliminating one allele of Rom1 (Rom1+/−) in three different Prph2 models which mimic human disease: C213Y Prph2 (Prph2C/+), K153Del Prph2 (Prph2K/+) and R172W (Prph2R172W).

Reducing Rom1 when there was no Prph2 mutations (Rom1+/−) had no effect on retinal structure or function. But
reducing Rom1 in the presence of Prph2 mutations were highly variable ranging from improved rod and cone function to worsened rod and cone function and exacerbated retinal degeneration.; to: PMID: 32716032 - Strayve et al 2020 - created mouse models to look at the effects of eliminating one allele of Rom1 (Rom1+/−) in three different Prph2 models which mimic human disease: C213Y Prph2 (Prph2C/+), K153Del Prph2 (Prph2K/+) and R172W (Prph2R172W).

Reducing Rom1 when there was no Prph2 mutations (Rom1+/−) had no effect on retinal structure or function. But reducing Rom1 in the presence of Prph2 mutations were highly variable ranging from improved rod and cone function to worsened rod and cone function and exacerbated retinal degeneration.
Cholestasis v1.25 USP53 Ivone Leong Publications for gene: USP53 were set to 30250217
Severe insulin resistance and lipodystrophy syndromes v2.7 POLR3GL Ivone Leong Classified gene: POLR3GL as Red List (low evidence)
Severe insulin resistance and lipodystrophy syndromes v2.7 POLR3GL Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There are 3 unrelated families with variants in this gene; however, lipodystrophy is only described in 1 family. Adding as Red gene until further evidence is available.
Severe insulin resistance and lipodystrophy syndromes v2.7 POLR3GL Ivone Leong Gene: polr3gl has been classified as Red List (Low Evidence).
Retinal disorders v2.16 ROM1 Eleanor Williams reviewed gene: ROM1: Rating: ; Mode of pathogenicity: None; Publications: 32716032; Phenotypes: retinal degeneration; Mode of inheritance: None
Hereditary neuropathy v1.377 SMN1 Eleanor Williams Publications for gene: SMN1 were set to
Paediatric motor neuronopathies v1.34 SMN1 Eleanor Williams Publications for gene: SMN1 were set to 7813012
Fetal anomalies v1.98 SMN1 Eleanor Williams Publications for gene: SMN1 were set to 11826188
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.8 SMN1 Eleanor Williams Publications for gene: SMN1 were set to
Hereditary spastic paraplegia, adult onset v1.12 Arina Puzriakova Panel version has been signed off
Arthrogryposis v3.14 SMN1 Eleanor Williams Publications for gene: SMN1 were set to 27911332; 10700538; 11826188; 8787675
Hereditary neuropathy or pain disorder v1.9 SMN1 Eleanor Williams Publications for gene: SMN1 were set to
Hereditary neuropathy or pain disorder v1.8 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Hereditary neuropathy v1.376 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Paediatric motor neuronopathies v1.33 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Fetal anomalies v1.97 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.59 Arina Puzriakova Panel version has been signed off
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.7 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Arthrogryposis v3.13 SMN1 Eleanor Williams edited their review of gene: SMN1: Changed phenotypes: Spinal muscular atrophy
Dystonia, chorea or related movement disorder, adult onset v1.14 Arina Puzriakova Panel version has been signed off
Arthrogryposis v3.13 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.14 Arina Puzriakova Panel version has been signed off
Hereditary spastic paraplegia, adult onset v1.10 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as No list
Hereditary spastic paraplegia, adult onset v1.10 HTT_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been removed at the request of GHLs for the GMS Neurology Specialist Test Group as it is available as a core test for R68 Huntington Disease. Inclusion on panels for other neurological CIs raises concerns regarding counselling, and so it has been agreed that HTT_CAG will be excluded from this panel.
Hereditary spastic paraplegia, adult onset v1.10 HTT_CAG Arina Puzriakova Str: htt_cag has been removed from the panel.
Hereditary spastic paraplegia, adult onset v1.9 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.9 ATXN10_ATTCT Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Hereditary spastic paraplegia, adult onset v1.9 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.20 JPH3_CTG Arina Puzriakova Classified STR: JPH3_CTG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.20 JPH3_CTG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Neurodegenerative disorders, adult onset v2.20 JPH3_CTG Arina Puzriakova Str: jph3_ctg has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.19 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.19 TBP_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Neurodegenerative disorders, adult onset v2.19 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.18 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v2.18 ATN1_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Neurodegenerative disorders, adult onset v2.18 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v2.17 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as No list
Neurodegenerative disorders, adult onset v2.17 HTT_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been removed at the request of GHLs for the GMS Neurology Specialist Test Group as it is available as a core test for R68 Huntington Disease. Inclusion on panels for other neurological CIs raises concerns regarding counselling, and so it has been agreed that HTT_CAG will be excluded from this panel.
Neurodegenerative disorders, adult onset v2.17 HTT_CAG Arina Puzriakova Str: htt_cag has been removed from the panel.
Dystonia, chorea or related movement disorder, adult onset v1.12 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as No list
Dystonia, chorea or related movement disorder, adult onset v1.12 HTT_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been removed at the request of GHLs for the GMS Neurology Specialist Test Group as it is available as a core test for R68 Huntington Disease. Inclusion on panels for other neurological CIs raises concerns regarding counselling, and so it has been agreed that HTT_CAG will be excluded from this panel.
Dystonia, chorea or related movement disorder, adult onset v1.12 HTT_CAG Arina Puzriakova Str: htt_cag has been removed from the panel.
Dystonia, chorea or related movement disorder, adult onset v1.11 PPP2R2B_CAG Arina Puzriakova Classified STR: PPP2R2B_CAG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.11 PPP2R2B_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.11 PPP2R2B_CAG Arina Puzriakova Str: ppp2r2b_cag has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v1.10 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.10 CSTB_CCCCGCCCCGCG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.10 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v1.9 CACNA1A_CAG Arina Puzriakova Classified STR: CACNA1A_CAG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.9 CACNA1A_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.9 CACNA1A_CAG Arina Puzriakova Str: cacna1a_cag has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v1.8 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.8 ATXN3_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.8 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v1.7 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.7 ATXN2_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.7 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v1.6 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.6 ATXN1_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.6 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.14 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as No list
Ataxia and cerebellar anomalies - childhood onset v2.14 HTT_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been removed at the request of GHLs for the GMS Neurology Specialist Test Group as it is available as a core test for R68 Huntington Disease. Inclusion on panels for other neurological CIs raises concerns regarding counselling, and so it has been agreed that HTT_CAG will be excluded from this panel.
Ataxia and cerebellar anomalies - childhood onset v2.14 HTT_CAG Arina Puzriakova Str: htt_cag has been removed from the panel.
Severe insulin resistance and lipodystrophy syndromes v2.6 MTX2 Ivone Leong Tag for-review tag was added to gene: MTX2.
Severe insulin resistance and lipodystrophy syndromes v2.6 MTX2 Ivone Leong Classified gene: MTX2 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v2.6 MTX2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. This gene will be rated Amber and promoted to Green at the next review of the panel.
Severe insulin resistance and lipodystrophy syndromes v2.6 MTX2 Ivone Leong Gene: mtx2 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v2.12 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as No list
Hereditary ataxia, adult onset v2.12 HTT_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been removed at the request of GHLs for the GMS Neurology Specialist Test Group as it is available as a core test for R68 Huntington Disease. Inclusion on panels for other neurological CIs raises concerns regarding counselling, and so it has been agreed that HTT_CAG will be excluded from this panel.
Hereditary ataxia, adult onset v2.12 HTT_CAG Arina Puzriakova Str: htt_cag has been removed from the panel.
Dilated and arrhythmogenic cardiomyopathy v1.6 TBX5 Ivone Leong Phenotypes for gene: TBX5 were changed from Holt-Oram syndrome, MIM# 142900; Dilated cardiomyopathy to Holt-Oram syndrome, 142900; Dilated cardiomyopathy
Holoprosencephaly v2.7 KMT2D Zornitza Stark gene: KMT2D was added
gene: KMT2D was added to Holoprosencephaly. Sources: Literature
Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2D were set to 31846209; 31282990; 32773771
Phenotypes for gene: KMT2D were set to Kabuki syndrome 1, MIM# 147920
Review for gene: KMT2D was set to GREEN
gene: KMT2D was marked as current diagnostic
Added comment: Three case reports of HPE in Kabuki syndrome. Association also observed by us internally, PMID 32773771, supplementary info.
Sources: Literature
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Classified gene: UGDH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families with severe epilepsy, mostly ranging from neonatal to infantile onset developmental epileptic encephalopathy.
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Gene: ugdh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.157 UGDH Arina Puzriakova Tag for-review tag was added to gene: UGDH.
Intellectual disability v3.379 UGDH Arina Puzriakova Classified gene: UGDH as Amber List (moderate evidence)
Intellectual disability v3.379 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families, all with moderate-to-severe ID in association with biallelic variants in UGDH.
Intellectual disability v3.379 UGDH Arina Puzriakova Gene: ugdh has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.378 UGDH Arina Puzriakova Tag for-review tag was added to gene: UGDH.
Non-CF bronchiectasis v1.26 DNAH5 Ivone Leong Classified gene: DNAH5 as Green List (high evidence)
Non-CF bronchiectasis v1.26 DNAH5 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert review from Zerin Hyder (Genomics England).
Non-CF bronchiectasis v1.26 DNAH5 Ivone Leong Gene: dnah5 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.25 DNAH5 Ivone Leong Publications for gene: DNAH5 were set to
Non-CF bronchiectasis v1.24 DNAH5 Ivone Leong Phenotypes for gene: DNAH5 were changed from Bronchiectasis to Bronchiectasis; Primary Ciliary Dyskinesia; Ciliary dyskinesia, primary, 3, with or without situs inversus, 608644; situs inversus
Non-CF bronchiectasis v1.23 DNAH5 Ivone Leong Mode of inheritance for gene: DNAH5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Pancreatitis v2.7 TRPV6 Ivone Leong Mode of inheritance for gene: TRPV6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Pancreatitis v2.6 TRPV6 Ivone Leong Classified gene: TRPV6 as Amber List (moderate evidence)
Pancreatitis v2.6 TRPV6 Ivone Leong Added comment: Comment on list classification: New gene added by Miranda Durkie. Based on the expert review this gene was added as an Amber gene.
Pancreatitis v2.6 TRPV6 Ivone Leong Gene: trpv6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Severe-to-profound DD and/or ID reported in all but one family with a milder phenotype (at least 9 total families described with different biallelic variants in SPTBN4).
Intellectual disability v3.378 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Pancreatitis v2.5 TRPV6 Ivone Leong Publications for gene: TRPV6 were set to PMID: 31930989; 32383311
Intellectual disability v3.377 SPTBN4 Arina Puzriakova Tag for-review tag was added to gene: SPTBN4.
Mitochondrial disorders v2.8 MT-ATP8 Ivone Leong commented on gene: MT-ATP8
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 7 unrelated cases presenting seizures, including tonic clonic, generalised, absence, and focal seizures.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 6 unrelated cases presenting epilepsy in association with different NR4A2 variants, including tonic clonic, generalised, absence, and focal seizures.
Primary lymphoedema v2.6 ANGPT2 Ivone Leong Tag for-review tag was added to gene: ANGPT2.
Primary lymphoedema v2.6 ANGPT2 Ivone Leong Classified gene: ANGPT2 as Amber List (moderate evidence)
Primary lymphoedema v2.6 ANGPT2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence for this gene to be rated Green, which will occur at the next major review/update.
Primary lymphoedema v2.6 ANGPT2 Ivone Leong Gene: angpt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Classified gene: NR4A2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 7 unrelated cases presenting seizures, including tonic clonic, generalised, absence, and focal seizures.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Gene: nr4a2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.156 NR4A2 Arina Puzriakova Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Early onset or syndromic epilepsy v2.155 NR4A2 Arina Puzriakova Tag for-review tag was added to gene: NR4A2.
Primary lymphoedema v2.5 FBXL7 Ivone Leong Classified gene: FBXL7 as Red List (low evidence)
Primary lymphoedema v2.5 FBXL7 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is only 1 case and therefore not enough evidence to support a gene-disease association.
Primary lymphoedema v2.5 FBXL7 Ivone Leong Gene: fbxl7 has been classified as Red List (Low Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.3 FOXE3 Ivone Leong Tag for-review tag was added to gene: FOXE3.
Hypertrophic cardiomyopathy v2.11 ALPK3 Ivone Leong Tag for-review tag was added to gene: ALPK3.
Hypertrophic cardiomyopathy v2.11 ALPK3 Ivone Leong Classified gene: ALPK3 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.11 ALPK3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease assocation for it to be Green. This gene will be promoted to Green at the next panel review.
Hypertrophic cardiomyopathy v2.11 ALPK3 Ivone Leong Gene: alpk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.377 NR4A2 Arina Puzriakova Classified gene: NR4A2 as Amber List (moderate evidence)
Intellectual disability v3.377 NR4A2 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).

The recent paper flagged by Konstantinos Varvagiannis (PMID:32366965) includes 2 unrelated patients with severe ID and 2 with moderate-severe ID. This is within the scope of the panel and the number of cases now reach threshold for inclusion with a Green rating.
Intellectual disability v3.377 NR4A2 Arina Puzriakova Gene: nr4a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.376 NR4A2 Arina Puzriakova Tag for-review tag was added to gene: NR4A2.
Intellectual disability v3.376 NR4A2 Arina Puzriakova Publications for gene: NR4A2 were set to 29770430; 30504930; 28544326; 27569545; 23554088; 28135719; 27479843; 25363768; https://doi.org/10.1101/516625
Hypertrophic cardiomyopathy v2.10 ALPK3 Ivone Leong Added comment: Comment on publications: PMID: 28630369. An additional case. Non-consanguineous family of Turkish decent. Fetus was homozgyous for variant and died at 30 weeks gestation. Heterozygous family members had normal cardiac function. Fetus also had dysmorphic facial features.

PMID: 30046096. An additional case. A consanguineous family of Tunisian decent. 3 year old affected with mixed HCM/DCM and dysmorphic features.

PMID: 31074094. An additional case. A family with 6 affected individuals.

PMID: 21441111. KO mouse model that replicates the human disease phenotype
Hypertrophic cardiomyopathy v2.10 ALPK3 Ivone Leong Publications for gene: ALPK3 were set to 26846950; 27106955; 32480058
Intellectual disability v3.375 TNRC6B Arina Puzriakova Tag for-review tag was added to gene: TNRC6B.
Intellectual disability v3.375 TNRC6B Arina Puzriakova Classified gene: TNRC6B as Amber List (moderate evidence)
Intellectual disability v3.375 TNRC6B Arina Puzriakova Added comment: Comment on list classification: This is a borderline Amber/Green gene, and should be reviewed at the date of next GMS panel update (added 'for-review' tag).

Phenotype is primarily characterised by neurobehavioral abnormalities, including DD (particularly speech impairment) in all cases, as well as variable features of autism, ADHD, impulsivity, anger and aggressiveness. Cognitive abilities were varied, and a formal diagnosis of ID was only attained in 4 patients. Nonetheless, this likely represents the most appropriate panel for capturing these cases and therefore a Green rating should be considered.
Intellectual disability v3.375 TNRC6B Arina Puzriakova Gene: tnrc6b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.374 TNRC6B Arina Puzriakova Phenotypes for gene: TNRC6B were changed from to Global developmental delay; Intellectual disability; Autistic behaviour
Intellectual disability v3.373 TNRC6B Arina Puzriakova Publications for gene: TNRC6B were set to
Intellectual disability v3.372 TNRC6B Arina Puzriakova Mode of inheritance for gene: TNRC6B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.371 STS Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Helen Brittain
Intellectual disability v3.371 STS Arina Puzriakova Classified gene: STS as Red List (low evidence)
Intellectual disability v3.371 STS Arina Puzriakova Gene: sts has been classified as Red List (Low Evidence).
Intellectual disability v3.370 STS Arina Puzriakova Added comment: Comment on publications: Added publication (PMID: 32139392) describing psychiatric/behavioural phenotypes in patients with ichthyosis caused by X-linked deletions spanning STS.
Intellectual disability v3.370 STS Arina Puzriakova Publications for gene: STS were set to
Respiratory ciliopathies including non-CF bronchiectasis v1.7 AKNA Zornitza Stark gene: AKNA was added
gene: AKNA was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: AKNA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKNA were set to 32367404; 21606955
Phenotypes for gene: AKNA were set to Primary ciliary dyskinesia
Review for gene: AKNA was set to RED
Added comment: PMID 32367404 :Two siblings with homozygous PTCs with PCD. Carrier parents and mutation negative siblings (5) were asymptomatic.

PMID: 21606955: Null mice have neonatal death with systemic inflammation and alveolar loss
Sources: Literature
Intestinal failure or congenital diarrhoea v1.5 AP1S1 Zornitza Stark gene: AP1S1 was added
gene: AP1S1 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: AP1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1S1 were set to 32306098
Phenotypes for gene: AP1S1 were set to Non-syndromic congenital intestinal failure
Review for gene: AP1S1 was set to AMBER
Added comment: - Established gene-disease association with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense variants.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.7 ITCH Zornitza Stark gene: ITCH was added
gene: ITCH was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: ITCH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITCH were set to 20170897; 32367404
Phenotypes for gene: ITCH were set to Autoimmune disease, multisystem, with facial dysmorphism 613385; primary ciliary dyskinesia
Review for gene: ITCH was set to RED
Added comment: Single individual with biallelic start-loss variant and primary ciliary dyskinesia reported in PMID 32367404.

Note that in the original Amish families, chronic lung disease was present in 9 of the 10 children, often clinically characterised as asthma and consisting of a cellular, nonspecific interstitial pneumonitis; respiratory failure was the cause of death in all 3 children who were deceased, at 6 months, 1.2 years, and 3 years of age, respectively. Unclear if ciliary dyskinesia may have been part of the phenotype.
Sources: Literature
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.101 SETD2 Ivone Leong Publications for gene: SETD2 were set to 29681085
Fetal anomalies v1.97 NUAK2 Zornitza Stark gene: NUAK2 was added
gene: NUAK2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NUAK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUAK2 were set to 32845958
Phenotypes for gene: NUAK2 were set to Anencephaly
Review for gene: NUAK2 was set to AMBER
Added comment: Novel gene described in single consanguineous family with three FDIU and extensive anencephaly. Hom inframe del affecting functional kinase domain, parents confirmed carriers. Good functional data showing loss of enzyme function and mouse model with 40% anencephaly after knock-out.
Sources: Literature
Monogenic hearing loss v2.94 THOC1 Zornitza Stark gene: THOC1 was added
gene: THOC1 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: THOC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THOC1 were set to 32776944
Phenotypes for gene: THOC1 were set to Nonsyndromic hearing loss
Review for gene: THOC1 was set to AMBER
Added comment: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the hypomorphic thoc1 in mouse induced hair cell apoptosis.
Sources: Literature
Hereditary neuropathy or pain disorder v1.8 GBF1 Zornitza Stark gene: GBF1 was added
gene: GBF1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: GBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBF1 were set to 32937143
Phenotypes for gene: GBF1 were set to Axonal Neuropathy
Review for gene: GBF1 was set to GREEN
gene: GBF1 was marked as current diagnostic
Added comment: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo). Age of onset varied from childhood (nonsense variant) to 50s. Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.7 GOLGA3 Zornitza Stark gene: GOLGA3 was added
gene: GOLGA3 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: GOLGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA3 were set to 23495255; 32367404
Phenotypes for gene: GOLGA3 were set to Primary ciliary dyskinesia
Review for gene: GOLGA3 was set to RED
Added comment: PMID 32367404: Two siblings with a homozygous missense and PCD. PMID: 23495255; null mice have failed spermatogenesis
Sources: Literature
Congenital myopathy v2.7 TNNT1 Arina Puzriakova reviewed gene: TNNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32994279; Phenotypes: Nemaline myopathy 5, Amish type, 605355, Nemaline Myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.20 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia
Review for gene: MBTPS1 was set to GREEN
gene: MBTPS1 was marked as current diagnostic
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v1.5 TBX5 Zornitza Stark gene: TBX5 was added
gene: TBX5 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Mode of inheritance for gene: TBX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX5 were set to 32449309; 32236096; 25963046; 25725155
Phenotypes for gene: TBX5 were set to Holt-Oram syndrome, MIM# 142900; Dilated cardiomyopathy
Review for gene: TBX5 was set to GREEN
gene: TBX5 was marked as current diagnostic
Added comment: 8 individuals from 4 unrelated families reported in PMID 32449309, relatively mild skeletal manifestations of HOS and DCM a prominent feature in several. Note previous reports, and supportive mouse model.
Sources: Literature
Proteinuric renal disease v2.26 IL1RAP Zornitza Stark gene: IL1RAP was added
gene: IL1RAP was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: IL1RAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL1RAP were set to 31954058
Phenotypes for gene: IL1RAP were set to Steroid-sensitive nephrotic syndrome
Review for gene: IL1RAP was set to RED
Added comment: A pair of siblings with compound heterozygous variants in this gene and steroid-sensitive nephrotic syndrome. Functional effect of variants demonstrated but mouse model does not have proteinuria.
Sources: Literature
Hypogonadotropic hypogonadism (GMS) v1.8 IGSF10 Zornitza Stark gene: IGSF10 was added
gene: IGSF10 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Literature
Mode of inheritance for gene: IGSF10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IGSF10 were set to 27137492; 31042289
Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency
Review for gene: IGSF10 was set to AMBER
Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance.
Sources: Literature
Early onset or syndromic epilepsy v2.155 KPTN Zornitza Stark edited their review of gene: KPTN: Added comment: Two further publications (PMID 32358097; 32808430), more individuals reported with seizures, suggest upgrade to Green.; Changed publications: 32358097, 32808430
Skeletal dysplasia v2.20 PFN1 Zornitza Stark gene: PFN1 was added
gene: PFN1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PFN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PFN1 were set to 32392277; 31991009; 31346562; 32589291; 22801503
Phenotypes for gene: PFN1 were set to Paget’s disease of bone
Review for gene: PFN1 was set to AMBER
Added comment: A new phenotype association for this gene has been reported: Paget’s disease of bone (PDB).
Haploinsuffciency has been linked to PDB in 2 families with the same truncating frameshift variant (unsure if the families are related, both families are from the same region in Italy). Functional studies of this truncating variant showed abnormal protein aggregates (PMID: 32392277, 31991009). An osteoclast-specific conditional null mouse model confirmed the skeletal phenotype (PMID: 31346562). Missense variants in this gene have been previously associated with ALS (PMID: 22801503). Due to these different phenotype associations, it has been suggested that this gene can cause multisystem proteinopathy (PMID: 32589291).
Sources: Literature
CAKUT v1.153 FOXC1 Zornitza Stark edited their review of gene: FOXC1: Changed rating: AMBER
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.100 SETD2 Ivone Leong Phenotypes for gene: SETD2 were changed from Luscan-Lumish syndrome, MIM#616831 to Luscan-Lumish syndrome, 616831
CAKUT v1.153 FOXC1 Zornitza Stark reviewed gene: FOXC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32475988; Phenotypes: Congenital anomalies of the kidney and urinary tract (CAKUT); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.9 BLOC1S5 Zornitza Stark gene: BLOC1S5 was added
gene: BLOC1S5 was added to Bleeding and platelet disorders. Sources: Literature
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome
Review for gene: BLOC1S5 was set to GREEN
gene: BLOC1S5 was marked as current diagnostic
Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2).

Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele.

Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.13 CAD Zornitza Stark gene: CAD was added
gene: CAD was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 32820246
Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50; OMIM # 616457
Review for gene: CAD was set to GREEN
Added comment: 2020 series: 6/20 patients reported had ataxia relating to cerebellar atrophy, which is an expansion to the phenotype.
Sources: Literature
Monogenic hearing loss v2.94 COCH Zornitza Stark reviewed gene: COCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 16151338, 28116169, 28099493, 9806553, 17561763, 21046548, 26256111, 22931125, 22610276, 18312449, 28733840, 18697796, 29449721, 32939038, 32562050; Phenotypes: Deafness, autosomal dominant 9, MIM# 601369, Deafness, autosomal recessive 110, MIM# 618094; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.26 RPS20 Zornitza Stark gene: RPS20 was added
gene: RPS20 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: RPS20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS20 were set to 32790018
Phenotypes for gene: RPS20 were set to Diamond Blackfan anaemia
Review for gene: RPS20 was set to AMBER
Added comment: Two unrelated cases where a de novo variant involving Ile84 (Ile84Ser and Ile84Asn), and reduce the RPS20 protein level in patient cells. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. Loss of function may not be the mechanism of disease, because loss of function variants appear to be exclusively associated with familial colorectal cancer without the DBA phenotype.
Sources: Literature
Monogenic hearing loss v2.94 LMX1A Zornitza Stark edited their review of gene: LMX1A: Added comment: Now 3 families with monoallelic missense variants (2 with dominant inheritance and 1 de novo), and a single biallelic family. Supporting mouse model and in vitro functional assays.; Changed rating: GREEN; Changed publications: 29754270, 29971487, 32840933
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.7 CAPN3 Arina Puzriakova Added comment: Comment on publications: Added publication to support association with this phenotype.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.7 CAPN3 Arina Puzriakova Publications for gene: CAPN3 were set to http://www.ncbi.nlm.nih.gov/books/NBK1408/
White matter disorders and cerebral calcification - childhood onset v1.16 KIAA1161 Zornitza Stark gene: KIAA1161 was added
gene: KIAA1161 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: KIAA1161 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KIAA1161 were set to 30656188; 30649222; 30460687; 29910000; 31951047
Review for gene: KIAA1161 was set to GREEN
Added comment: PMID 31951047: In a cohort study comprising 435 individuals with primary brain calcification, 38 individuals identified with mono-allelic variants in this gene, in addition to 14 with bi-allelic variants. Clinical and imaging penetrance of individuals with bi-allelic variants were 100%, whereas among individuals with heterozygous variants, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG variants, individuals with heterozygous variants had brain calcifications with much lower calcification scores (P < 2e-16). HGNC approved name is MYORG.

Note additional publications supporting association with bi-allelic variants.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.16 PCYT2 Arina Puzriakova Classified gene: PCYT2 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.16 PCYT2 Arina Puzriakova Added comment: Comment on list classification: The rating of this gene should be reviewed at the next GMS panel update. Based on the review by Rebecca Foulger, there is sufficient evidence to rate this gene Green.
Hereditary spastic paraplegia, childhood onset v2.16 PCYT2 Arina Puzriakova Gene: pcyt2 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, adult onset v1.8 PCYT2 Arina Puzriakova changed review comment from: Comment on list classification: The rating of this gene should be reviewed at the next GMS panel update.
Based on the review by Rebecca Foulger, there is sufficient evidence to rate this gene Green.; to: Comment on list classification: The rating of this gene should be reviewed at the next GMS panel update. Based on the review by Rebecca Foulger, there is sufficient evidence to rate this gene Green.
Hereditary spastic paraplegia, adult onset v1.8 PCYT2 Arina Puzriakova Classified gene: PCYT2 as Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.8 PCYT2 Arina Puzriakova Added comment: Comment on list classification: The rating of this gene should be reviewed at the next GMS panel update.
Based on the review by Rebecca Foulger, there is sufficient evidence to rate this gene Green.
Hereditary spastic paraplegia, adult onset v1.8 PCYT2 Arina Puzriakova Gene: pcyt2 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.8 TCF12 Zornitza Stark gene: TCF12 was added
gene: TCF12 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Literature
Mode of inheritance for gene: TCF12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF12 were set to 23354436; 32620954
Phenotypes for gene: TCF12 were set to Craniosynostosis 3, MIM# 615314; Kallman syndrome
Review for gene: TCF12 was set to GREEN
Added comment: Well established gene-disease association with craniosynostosis with 38 unrelated families reported in the original gene discovery paper alone. New association with Kallman syndrome reported in PMID 32620954 (13 families, all but one mono-allelic variants), though note some individuals also had craniosynostosis so may represent a spectrum.
Sources: Literature
Severe insulin resistance and lipodystrophy syndromes v2.5 MTX2 Zornitza Stark gene: MTX2 was added
gene: MTX2 was added to Lipodystrophy - childhood onset. Sources: Literature
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Review for gene: MTX2 was set to GREEN
Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation.
Sources: Literature
RASopathies v1.61 RREB1 Zornitza Stark gene: RREB1 was added
gene: RREB1 was added to RASopathies. Sources: Literature
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to 32938917
Phenotypes for gene: RREB1 were set to Noonan syndrome-like disorder
Review for gene: RREB1 was set to RED
Added comment: Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes. In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.16 FARSA Zornitza Stark gene: FARSA was added
gene: FARSA was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Review for gene: FARSA was set to RED
Added comment: Autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts. Single affected individual reported, but FARSA interacts with FARSB, which causes a similar disorder.
Sources: Literature
Primary lymphoedema v2.4 ANGPT2 Zornitza Stark gene: ANGPT2 was added
gene: ANGPT2 was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: ANGPT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT2 were set to 32908006
Phenotypes for gene: ANGPT2 were set to Primary lymphoedema
Review for gene: ANGPT2 was set to GREEN
Added comment: Five unrelated individuals reported with primary lymphedema and variants in this gene, together with functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.199 STAT4 Boaz Palterer reviewed gene: STAT4: Rating: RED; Mode of pathogenicity: None; Publications: 29029192; Phenotypes: Paracoccidioidomycosis, Impaired IFN-γ Immunity; Mode of inheritance: Unknown
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides produced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration in mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis changed review comment from: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature; to: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could be ruled out that the de novo and maternally inherited variants were on the same allele, as phase was not been determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Intellectual disability v3.369 NEMF Konstantinos Varvagiannis gene: NEMF was added
gene: NEMF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NEMF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Hypotonia; Global developmental delay; Intellectual disability; Axonal neuropathy; Ataxia; Abnormal brain imaging; Kyphosis; Scoliosis; Tremor; Respiratory distress
Penetrance for gene: NEMF were set to Complete
Review for gene: NEMF was set to GREEN
Added comment: Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides prodduced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration im mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Arthrogryposis v3.13 SCN1A Zornitza Stark edited their review of gene: SCN1A: Changed phenotypes: Arthrogryposis multiplex congenita, Dravet syndrome, MIM# 607208
Arthrogryposis v3.13 SCN1A Zornitza Stark reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32928894, 29543227; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v3.13 SCN1A Arina Puzriakova commented on gene: SCN1A: Note SCN1A is a well-established cause of Dravet syndrome, MIM# 607208
Arthrogryposis v3.13 SCN1A Arina Puzriakova changed review comment from: Comment on list classification: Association with this phenotype currently based on a single publication, although reporting 3 unrelated cases.

Rating Amber, awaiting further publications/clinical evidence to validate this gene-disease association.; to: Comment on list classification: Association with this phenotype currently based on a single publication, although reporting 3 unrelated cases.

Rating Amber, awaiting further publications/clinical evidence to validate this gene-disease relationship.
Arthrogryposis v3.13 SCN1A Arina Puzriakova Classified gene: SCN1A as Amber List (moderate evidence)
Arthrogryposis v3.13 SCN1A Arina Puzriakova Added comment: Comment on list classification: Association with this phenotype currently based on a single publication, although reporting 3 unrelated cases.

Rating Amber, awaiting further publications/clinical evidence to validate this gene-disease association.
Arthrogryposis v3.13 SCN1A Arina Puzriakova Gene: scn1a has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.12 SCN1A Arina Puzriakova gene: SCN1A was added
gene: SCN1A was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: SCN1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCN1A were set to 32928894
Phenotypes for gene: SCN1A were set to Arthrogryposis multiplex congenita
Review for gene: SCN1A was set to AMBER
Added comment: PMID: 32928894 (2020) - De novo missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three unrelated patients with AMC which was diagnosed from the second trimester of pregnancy. One patient developed intractable epilepsy from birth and died at 21 days, while the other two pregnancies were terminated. No functional studies of the variants or patient cells were performed.
Sources: Literature
Familial melanoma v1.7 POT1 Arina Puzriakova Tag for-review tag was added to gene: POT1.
Familial melanoma v1.7 POT1 Arina Puzriakova Phenotypes for gene: POT1 were changed from to Melanoma, cutaneous malignant, susceptibility to, 10, 615848
Familial melanoma v1.6 POT1 Arina Puzriakova Publications for gene: POT1 were set to
Familial melanoma v1.5 POT1 Arina Puzriakova Classified gene: POT1 as Amber List (moderate evidence)
Familial melanoma v1.5 POT1 Arina Puzriakova Added comment: Comment on list classification: Based on evidence provided by several publications, POT1 should be considered for a rating upgrade from Amber to Green, and therefore will be flagged for review at the date of next GMS panel update (added 'for-review' tag).
Familial melanoma v1.5 POT1 Arina Puzriakova Gene: pot1 has been classified as Amber List (Moderate Evidence).
Familial melanoma v1.4 POT1 Arina Puzriakova edited their review of gene: POT1: Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial melanoma v1.4 POT1 Arina Puzriakova reviewed gene: POT1: Rating: ; Mode of pathogenicity: None; Publications: 24686849, 24686846, 29523635, 30451293, 30586141, 32325837; Phenotypes: Melanoma, cutaneous malignant, susceptibility to, 10, 615848; Mode of inheritance: None
Hereditary haemorrhagic telangiectasia v2.6 RASA1 Arina Puzriakova Tag for-review tag was added to gene: RASA1.
Hereditary haemorrhagic telangiectasia v2.6 RASA1 Arina Puzriakova Publications for gene: RASA1 were set to 18446851; 27081547
Hereditary haemorrhagic telangiectasia v2.5 RASA1 Arina Puzriakova Classified gene: RASA1 as Red List (low evidence)
Hereditary haemorrhagic telangiectasia v2.5 RASA1 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).

Given the phenotypic overlap with HHT, these patients are likely to benefit from inclusion of RASA1 on a HHT panel, aiding detection rate and accurate diagnosis. Therefore, a rating upgrade from Red to Green should be considered.
Hereditary haemorrhagic telangiectasia v2.5 RASA1 Arina Puzriakova Gene: rasa1 has been classified as Red List (Low Evidence).
Hereditary haemorrhagic telangiectasia v2.4 RASA1 Arina Puzriakova reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27081547, 29891884, 32900839; Phenotypes: Capillary malformation-arteriovenous malformation 1, 608354; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.369 PRKD1 Arina Puzriakova changed review comment from: Gene included previously in context of publication by Sifrim et al. (2016) (PMID: 27479907).
However, re-evaluation of this paper showed that only two of the three patients had ID, which may possibly be associated with microcephaly. The two individuals carried a c.1774G>A and c.896T>G variant, respectively; however, a third patient also harbouring the c.1774G>A variant did not display any neuropsychological signs (or microcephaly) at 4.86 years (see supplementary table 12).

A recent report (PMID: 32817298, 2020) describes two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. These patients shared cardiac and ectodermal abnormalities, as with the previously described patients; however, mental development was normal in both individuals.; to: Gene included previously in context of publication by Sifrim et al. (2016) (PMID: 27479907).
However, re-evaluation of this paper showed that only two of the three patients had ID, which may possibly be associated with microcephaly. The two individuals carried a c.1774G>A and c.896T>G variant, respectively; however, a third patient also harbouring the c.1774G>A variant did not display any neuropsychological signs (or microcephaly) at 4.86 years (see supplementary table 12, and figure 3).

A recent report (PMID: 32817298, 2020) describes two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. These patients shared cardiac and ectodermal abnormalities, as with the previously described patients; however, mental development was normal in both individuals.
Ectodermal dysplasia v1.8 PRKD1 Arina Puzriakova Classified gene: PRKD1 as Amber List (moderate evidence)
Ectodermal dysplasia v1.8 PRKD1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to support a gene-disease association. Therefore, PRKD1 should be upgraded from Amber to Green at the next major review.
Ectodermal dysplasia v1.8 PRKD1 Arina Puzriakova Gene: prkd1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.7 PRKD1 Arina Puzriakova gene: PRKD1 was added
gene: PRKD1 was added to Ectodermal dysplasia. Sources: Literature
for-review tags were added to gene: PRKD1.
Mode of inheritance for gene: PRKD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKD1 were set to 27479907; 32817298
Phenotypes for gene: PRKD1 were set to Congenital heart defects and ectodermal dysplasia, 617364
Review for gene: PRKD1 was set to GREEN
Added comment: PMID: 27479907 (2016) - Three unrelated cases with de novo missense variants in the PRKD1 gene. Variable characteristics of ectodermal dysplasia included sparse hair, dry or thin skin, fragile nails, and dental abnormalities (premature loss of primary teeth, small widely spaced teeth). Additional features include atrioventricular septal defects or pulmonic stenosis, severe developmental delay and microcephaly. No functional studies of the variants were performed.

PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, respectively. Both displayed features of ectodermal dysplasia such as dry skin, absence of permanent teeth and poor hair growth. Other features included congenital heart defects, skeletal abnormalities and generalised teleangiectasia.
Sources: Literature
Intellectual disability v3.369 PRKD1 Arina Puzriakova Classified gene: PRKD1 as Green List (high evidence)
Intellectual disability v3.369 PRKD1 Arina Puzriakova Added comment: Comment on list classification: This gene has been flagged for review at the date of next GMS panel update (added 'for-review' tag).

Only 2/5 patients exhibit features of ID, both of whom were also the only microcephalic cases, indicating the possibility of additional contributing factors. Therefore, a rating downgrade from Green to Amber may be warranted.
Intellectual disability v3.369 PRKD1 Arina Puzriakova Gene: prkd1 has been classified as Green List (High Evidence).
Intellectual disability v3.368 PRKD1 Arina Puzriakova Publications for gene: PRKD1 were set to 27479907; 25529582
Intellectual disability v3.367 PRKD1 Arina Puzriakova Tag for-review tag was added to gene: PRKD1.
Intellectual disability v3.367 PRKD1 Arina Puzriakova reviewed gene: PRKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.97 GREB1L Rhiannon Mellis reviewed gene: GREB1L: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 31424080, 32378186; Phenotypes: Renal agenesis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Classified gene: CUL3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on external expert review and evidence provided by Konstantinos Varvagiannis. Only two unrelated cases reported and therefore not yet reaching threshold for inclusion.
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Gene: cul3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.367 CUL3 Arina Puzriakova Phenotypes for gene: CUL3 were changed from to Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496
Intellectual disability v3.366 CUL3 Arina Puzriakova Publications for gene: CUL3 were set to
Intellectual disability v3.365 CUL3 Arina Puzriakova Mode of inheritance for gene: CUL3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.364 CUL3 Arina Puzriakova Classified gene: CUL3 as Amber List (moderate evidence)
Intellectual disability v3.364 CUL3 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, as some cases reported with severe features of ID but not yet reaching the threshold for inclusion. Additional cases/publications would also enable clarification regarding the contribution of seizures to this phenotype.
Intellectual disability v3.364 CUL3 Arina Puzriakova Gene: cul3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.363 CUL3 Arina Puzriakova commented on gene: CUL3: Literature search showed that CUL3 variants are often found in ASD patients, however the association with ID is much less discernible. Only two cases reported to date with severe ID features, but the same two individuals were also the only ones to present early-onset seizures. Therefore, it is difficult to distinguish whether these findings were independent of one another.
Intellectual disability v3.363 CUL3 Arina Puzriakova changed review comment from: - PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances and ADHD.; to: - PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances, ADHD, and no seizures. No functional analysis was undertaken.
Intellectual disability v3.363 CUL3 Arina Puzriakova reviewed gene: CUL3: Rating: ; Mode of pathogenicity: None; Publications: 25969726; Phenotypes: Autism spectrum disorder, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dystonia, chorea or related movement disorder, childhood onset v1.57 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.57 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.56 CSTB_CCCCGCCCCGCG Arina Puzriakova STR: CSTB_CCCCGCCCCGCG was added
STR: CSTB_CCCCGCCCCGCG was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
STR tags were added to STR: CSTB_CCCCGCCCCGCG.
Mode of inheritance for STR: CSTB_CCCCGCCCCGCG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for STR: CSTB_CCCCGCCCCGCG were set to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800
Review for STR: CSTB_CCCCGCCCCGCG was set to GREEN
Added comment: New STR submitted and discussed with GLHs for the GMS Neurology Specialist Test Group, who agreed that there is sufficient evidence to rate this STR Green on this panel.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.55 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.55 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Green List (High Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.54 TBP_CAG Arina Puzriakova STR: TBP_CAG was added
STR: TBP_CAG was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
STR tags were added to STR: TBP_CAG.
Mode of inheritance for STR: TBP_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: TBP_CAG were set to Spinocerebellar ataxia 17, 607136
Review for STR: TBP_CAG was set to GREEN
STR: TBP_CAG was marked as current diagnostic
Added comment: New STR submitted and discussed with GLHs for the GMS Neurology Specialist Test Group, who agreed that there is sufficient evidence to rate this STR Green on this panel.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.53 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.53 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.52 ATXN2_CAG Arina Puzriakova STR: ATXN2_CAG was added
STR: ATXN2_CAG was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
STR tags were added to STR: ATXN2_CAG.
Mode of inheritance for STR: ATXN2_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN2_CAG were set to Spinocerebellar ataxia 2, 183090
Review for STR: ATXN2_CAG was set to GREEN
STR: ATXN2_CAG was marked as current diagnostic
Added comment: New STR submitted and discussed with GLHs for the GMS Neurology Specialist Test Group, who agreed that there is sufficient evidence to rate this STR Green on this panel.
Sources: Expert list
Hereditary ataxia, adult onset v2.11 FMR1_CGG Arina Puzriakova Classified STR: FMR1_CGG as Green List (high evidence)
Hereditary ataxia, adult onset v2.11 FMR1_CGG Arina Puzriakova Str: fmr1_cgg has been classified as Green List (High Evidence).
Hereditary ataxia, adult onset v2.10 FMR1_CGG Arina Puzriakova STR: FMR1_CGG was added
STR: FMR1_CGG was added to Hereditary ataxia - adult onset. Sources: Expert list
STR tags were added to STR: FMR1_CGG.
Mode of inheritance for STR: FMR1_CGG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for STR: FMR1_CGG were set to Fragile X syndrome, 300624
Review for STR: FMR1_CGG was set to GREEN
Added comment: New STR submitted and discussed with GLHs for the GMS Neurology Specialist Test Group, who agreed that there is sufficient evidence to rate this STR Green on this panel.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.26 RPL9 Arina Puzriakova Classified gene: RPL9 as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.26 RPL9 Arina Puzriakova Added comment: Comment on list classification: Current Green rating is based on consensus from GLHs, so will remain Green.
Cytopenia - NOT Fanconi anaemia v1.26 RPL9 Arina Puzriakova Gene: rpl9 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v1.25 RPL9 Arina Puzriakova reviewed gene: RPL9: Rating: ; Mode of pathogenicity: None; Publications: 20116044, 29114930, 31799629; Phenotypes: Diamond Blackfan anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cytopenia - NOT Fanconi anaemia v1.25 RPL26 Arina Puzriakova changed review comment from: To date, only a single individual has been reported with Diamond-Blackfan anemia due to a de novo 2-nucleotide deletion in RPL26. Includes some in vitro functional data indicating the variants impairs RPL26 function in ribosome biogenesis (PMID: 22431104); to: To date, only a single individual has been reported with Diamond-Blackfan anemia due to a de novo 2-nucleotide deletion in RPL26. Includes some in vitro functional data indicating the variant impairs RPL26 function in ribosome biogenesis (PMID: 22431104)
Cytopenia - NOT Fanconi anaemia v1.25 RPL26 Arina Puzriakova Tag for-review tag was added to gene: RPL26.
Cytopenia - NOT Fanconi anaemia v1.25 RPL26 Arina Puzriakova Classified gene: RPL26 as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.25 RPL26 Arina Puzriakova Added comment: Comment on list classification: Current Green rating is based on consensus from GLHs, so will remain Green. However, this gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).
Cytopenia - NOT Fanconi anaemia v1.25 RPL26 Arina Puzriakova Gene: rpl26 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v1.24 RPL26 Arina Puzriakova reviewed gene: RPL26: Rating: ; Mode of pathogenicity: None; Publications: 22431104; Phenotypes: Diamond-Blackfan anemia 11, 614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult solid tumours cancer susceptibility v2.5 NOP10 Arina Puzriakova Phenotypes for gene: NOP10 were changed from Dyskeratosis Congenita to Dyskeratosis congenita, autosomal recessive 1, 224230
Childhood solid tumours cancer susceptibility v1.14 NOP10 Arina Puzriakova Phenotypes for gene: NOP10 were changed from Dyskeratosis Congenita to Dyskeratosis congenita, autosomal recessive 1, 224230
Ductal plate malformation v1.11 NOP10 Arina Puzriakova Phenotypes for gene: NOP10 were changed from Dyskeratosis congenita, autosomal recessive 1 (224230) to Dyskeratosis congenita, autosomal recessive 1, 224230
Pigmentary skin disorders v1.4 NOP10 Arina Puzriakova Phenotypes for gene: NOP10 were changed from DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 1, 224230 to Dyskeratosis congenita, autosomal recessive 1, 224230
Childhood solid tumours v2.14 NOP10 Arina Puzriakova Phenotypes for gene: NOP10 were changed from Dyskeratosis Congenita to Dyskeratosis congenita, autosomal recessive 1, 224230
Cytopenia - NOT Fanconi anaemia v1.24 NOP10 Arina Puzriakova Phenotypes for gene: NOP10 were changed from Dyskeratosis congenita, autosomal recessive 1, 224230; 224230 Dyskeratosis congenita, autosomal recessive 1 to Dyskeratosis congenita, autosomal recessive 1, 224230
Cytopenia - NOT Fanconi anaemia v1.23 NOP10 Arina Puzriakova reviewed gene: NOP10: Rating: ; Mode of pathogenicity: None; Publications: 17507419; Phenotypes: Dyskeratosis congenita, autosomal recessive 1, 224230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood solid tumours v2.13 NOP10 Arina Puzriakova changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Homozygous NOP10 variant (c.100C>T, p.Arg34Trp) only reported once in 3 affected members of a consanguineous Saudi family (PMID: 17507419). Additional cases required before inclusion on a diagnostic panel.; to: Comment on list classification: Associated with relevant phenotype in OMIM and a possible Gen2Phen gene. Homozygous NOP10 variant (c.100C>T, p.Arg34Trp) only reported once in 3 affected members of a consanguineous Saudi family (PMID: 17507419). Additional cases required before inclusion on a diagnostic panel, therefore left Amber until further evidence to support Green rating by external expert
Cytopenias and congenital anaemias v1.77 NHP2 Arina Puzriakova Classified gene: NHP2 as Green List (high evidence)
Cytopenias and congenital anaemias v1.77 NHP2 Arina Puzriakova Added comment: Comment on list classification: With addition of the recent paper (PMID:31985013), there are now a total of 3 unrelated cases with dyskeratosis congenita due to biallelic variants in NHP2, as well as supportive in vitro data.

Cases now reach threshold for inclusion and therefore, the rating for NHP2 has been promoted from Amber to Green.
Cytopenias and congenital anaemias v1.77 NHP2 Arina Puzriakova Gene: nhp2 has been classified as Green List (High Evidence).
Cytopenias and congenital anaemias v1.76 NHP2 Arina Puzriakova reviewed gene: NHP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, 613987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenias and congenital anaemias v1.76 NHP2 Arina Puzriakova Phenotypes for gene: NHP2 were changed from Dyskeratosis congenita, autosomal recessive 2 613987 to Dyskeratosis congenita, autosomal recessive 2, 613987
Cytopenias and congenital anaemias v1.75 NHP2 Arina Puzriakova Publications for gene: NHP2 were set to 18523010
Intellectual disability v3.363 NHP2 Arina Puzriakova Classified gene: NHP2 as Amber List (moderate evidence)
Intellectual disability v3.363 NHP2 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber as 2/3 cases described in literature present cognitive impairment. This does not yet meet the threshold for inclusion with a Green rating, but may be reviewed if further cases are published.
Intellectual disability v3.363 NHP2 Arina Puzriakova Gene: nhp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.362 NHP2 Arina Puzriakova Phenotypes for gene: NHP2 were changed from Dyskeratosis congenita, autosomal recessive 2, 613987 to Dyskeratosis congenita, autosomal recessive 2, 613987; Høyeraal-Hreidarsson syndrome
Intellectual disability v3.361 NHP2 Arina Puzriakova Publications for gene: NHP2 were set to 25182133; 18523010; 25907943; 20301779
Fetal anomalies v1.97 AGRN Rhiannon Mellis reviewed gene: AGRN: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 31730230; Phenotypes: Fetal akinesia deformation sequence; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.23 NHP2 Arina Puzriakova Phenotypes for gene: NHP2 were changed from 613987 Dyskeratosis congenita, autosomal recessive 2; Dyskeratosis congenita, autosomal recessive 2, 613987; Dyskeratosis congenita, autosomal recessive 2,613987 to Dyskeratosis congenita, autosomal recessive 2, 613987
Cytopenia - NOT Fanconi anaemia v1.22 NHP2 Arina Puzriakova Publications for gene: NHP2 were set to 18523010
Cytopenia - NOT Fanconi anaemia v1.21 NHP2 Arina Puzriakova Tag for-review tag was added to gene: NHP2.
Cytopenia - NOT Fanconi anaemia v1.21 NHP2 Arina Puzriakova Classified gene: NHP2 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.21 NHP2 Arina Puzriakova Added comment: Comment on list classification: With addition of the recent paper flagged by Zornitza Stark (PMID:31985013), there is now a total of 3 unrelated cases with dyskeratosis congenita due to biallelic variants in NHP2, as well as supportive in vitro data.

Cases now reach threshold for inclusion and therefore, NHP2 should be promoted from Amber to Green at the next major review.
Cytopenia - NOT Fanconi anaemia v1.21 NHP2 Arina Puzriakova Gene: nhp2 has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.20 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Panel version has been signed off
Hereditary Erythrocytosis v1.19 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease
Panel version has been signed off
Hereditary Erythrocytosis v1.17 SH2B3 Arina Puzriakova Tag for-review was removed from gene: SH2B3.
Hereditary Erythrocytosis v1.17 SH2B3 Arina Puzriakova Mode of inheritance for gene: SH2B3 was changed from Unknown to Other
Hereditary Erythrocytosis v1.16 JAK2 Arina Puzriakova Tag for-review was removed from gene: JAK2.
Thrombocythaemia v1.2 Arina Puzriakova Panel version has been signed off
Thrombocythaemia v1.0 Arina Puzriakova promoted panel to version 1.0
Thrombocythaemia v0.11 Arina Puzriakova Panel types changed to GMS Rare Disease; GMS signed-off
Thrombocythaemia v0.10 SH2B3 Arina Puzriakova Mode of inheritance for gene: SH2B3 was changed from Unknown to Other
Thrombocythaemia v0.9 CALR Arina Puzriakova Mode of inheritance for gene: CALR was changed from Unknown to Other
Intellectual disability v3.360 SETD1A Zerin Hyder reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32346159; Phenotypes: Epilepsy, early-onset, with or without developmental delay, craniofacial dysmorphisms, behavioural/psychiatric abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.20 MYSM1 Arina Puzriakova Phenotypes for gene: MYSM1 were changed from 618116 Bone marrow failure syndrome 4 to Bone marrow failure syndrome 4, 618116
Cytopenia - NOT Fanconi anaemia v1.19 MYSM1 Arina Puzriakova Publications for gene: MYSM1 were set to
Cytopenia - NOT Fanconi anaemia v1.18 MYSM1 Arina Puzriakova Classified gene: MYSM1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.18 MYSM1 Arina Puzriakova Added comment: Comment on list classification: There are enough cases to support a gene-disease association, as well as several corroborative animal models. Therefore, there is sufficient evidence for MYSM1 to be upgraded from Amber to Green at the next major review.
Cytopenia - NOT Fanconi anaemia v1.18 MYSM1 Arina Puzriakova Gene: mysm1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.17 MYSM1 Arina Puzriakova Tag for-review tag was added to gene: MYSM1.
Cytopenia - NOT Fanconi anaemia v1.17 KIF23 Arina Puzriakova changed review comment from: Comment on list classification: Literature search showed KIF23 is a widely accepted cause of CDA type III, albeit only two families with the same variant have been published.

Furthermore, current Green rating based on consensus from GLHs, so will remain Green. However, this gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).; to: Comment on list classification: Literature search showed KIF23 is a widely accepted cause of CDA type III, albeit only two families with the same variant have been published.

Furthermore, current Green rating is based on consensus from GLHs, so will remain Green. However, this gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).
Cytopenia - NOT Fanconi anaemia v1.17 KIF23 Arina Puzriakova Tag for-review tag was added to gene: KIF23.
Cytopenia - NOT Fanconi anaemia v1.17 KIF23 Arina Puzriakova Classified gene: KIF23 as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.17 KIF23 Arina Puzriakova Added comment: Comment on list classification: Literature search showed KIF23 is a widely accepted cause of CDA type III, albeit only two families with the same variant have been published.

Furthermore, current Green rating based on consensus from GLHs, so will remain Green. However, this gene will be flagged for review at the date of next GMS panel update (added 'for-review' tag).
Cytopenia - NOT Fanconi anaemia v1.17 KIF23 Arina Puzriakova Gene: kif23 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v1.16 KIF23 Arina Puzriakova reviewed gene: KIF23: Rating: ; Mode of pathogenicity: None; Publications: 23570799; Phenotypes: Congenital dyserythropoietic anemia type III; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.360 CYP2U1 Eleanor Williams Tag for-review tag was added to gene: CYP2U1.
Intellectual disability v3.360 CYP2U1 Eleanor Williams Classified gene: CYP2U1 as Green List (high evidence)
Intellectual disability v3.360 CYP2U1 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green for now, but after consultation with the Genomics England clinical team it was felt that it should be considered for downgrade to amber at the next GMS review. It is a spastic paraplegia gene and seems to mainly present in that manner. Amber rating would be appropriate as cognitive impairment is a feature and new cases may emerge which support that as a primary presentation.
Intellectual disability v3.360 CYP2U1 Eleanor Williams Gene: cyp2u1 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.16 NUP188 Arina Puzriakova Classified gene: NUP188 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.16 NUP188 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next major review - abnormalities on brain MRI are reported in all affected individuals to date, including loss of white matter (4/8) and delayed myelination (5/8)
White matter disorders and cerebral calcification - childhood onset v1.16 NUP188 Arina Puzriakova Gene: nup188 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.15 NUP188 Arina Puzriakova gene: NUP188 was added
gene: NUP188 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
for-review tags were added to gene: NUP188.
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 32275884
Phenotypes for gene: NUP188 were set to Sandestig-Stefanova syndrome, 618804
Review for gene: NUP188 was set to GREEN
Added comment: Associated with Sandestig-Stefanova syndrome in OMIM, but not yet in G2P.

- PMID: 32021605 (2020) - Two unrelated patients with different homozygous nonsense variants of NUP188, c.287dupA, p.Tyr96* and c.337C>T, p.Gln113*, respectively. Authors note strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, ventricular septal defect, and brain MRI anomalies (ventriculomegaly, loss of periventricular white matter, thin corpus callosum, and delayed myelination). Both ultimately died as a result of central respiratory failure at the age of 67 and 140 days, respectively.

- PMID: 32275884 (2020) - Six individuals from four unrelated families with bi-allelic truncating variants in NUP188 and similar phenotypes characterised by prenatal-onset ventriculomegaly or suspected brain malformation (4/6), congenital cataracts (4/6), congenital heart defects (5/5), hypotonia (5/6), brain MRI abnormalities (6/6) including ventriculomegaly loss of white-matter, hypoplastic corpus callosum, and delayed myelination. Progressive microcephaly consistent with a neurodegenerative process was noted in at least 3 cases. All six patients died of respiratory failure or respiratory-related illness: five within the first seven months of life; and the sixth at 2 years and 7 months, who also has severe ID and was non-ambulatory.
Sources: Literature
Severe microcephaly v2.26 NUP188 Arina Puzriakova Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract; structural brain abnormalities; hypoventilation to Sandestig-Stefanova syndrome, 618804
Severe microcephaly v2.25 NUP188 Arina Puzriakova Classified gene: NUP188 as Amber List (moderate evidence)
Severe microcephaly v2.25 NUP188 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next major review - progressive microcephaly reported in at least 5 affected individuals due to biallelic truncating variants in NUP188.
Severe microcephaly v2.25 NUP188 Arina Puzriakova Gene: nup188 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.24 NUP188 Arina Puzriakova Tag for-review tag was added to gene: NUP188.
Severe microcephaly v2.24 NUP188 Arina Puzriakova reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanova syndrome, 618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.15 NUP188 Arina Puzriakova Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract; structural brain abnormalities; hypoventilation to Sandestig-Stefanova syndrome, 618804
Bilateral congenital or childhood onset cataracts v2.14 NUP188 Arina Puzriakova Classified gene: NUP188 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.14 NUP188 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next major review - congenital cataract reported in at least 6 affected individuals (5 unrelated kindreds) due to biallelic truncating variants in NUP188.
Bilateral congenital or childhood onset cataracts v2.14 NUP188 Arina Puzriakova Gene: nup188 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.13 NUP188 Arina Puzriakova Tag for-review tag was added to gene: NUP188.
Bilateral congenital or childhood onset cataracts v2.13 NUP188 Arina Puzriakova reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanova syndrome, 618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.359 NUP188 Arina Puzriakova Phenotypes for gene: NUP188 were changed from to Sandestig-Stefanova syndrome, 618804
Intellectual disability v3.358 NUP188 Arina Puzriakova Publications for gene: NUP188 were set to
Intellectual disability v3.357 NUP188 Arina Puzriakova Mode of inheritance for gene: NUP188 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.356 NUP188 Arina Puzriakova Classified gene: NUP188 as Amber List (moderate evidence)
Intellectual disability v3.356 NUP188 Arina Puzriakova Added comment: Comment on list classification: At least six unrelated families exhibiting a strikingly similar phenotype due to biallelic truncating variants in the NUP188 gene. Only 1/8 individuals survived beyond the first year of life and exhibited severe ID.

It is anticipated that other surviving patients would likely present the same phenotype; however, for now NUP188 will be rated Amber on the ID panel, awaiting further publications to corroborate the relevance of this manifestation.
Intellectual disability v3.356 NUP188 Arina Puzriakova Gene: nup188 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.355 NUP188 Arina Puzriakova reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanova syndrome, 618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the JAK2 (V617F) variant. Influence of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the known JAK2 (V617F) somatic variant. The role of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype with these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the JAK2 (V617F) variant. Influence of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR
Intellectual disability v3.355 INTS6 Arina Puzriakova Classified gene: INTS6 as Red List (low evidence)
Intellectual disability v3.355 INTS6 Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.355 INTS6 Arina Puzriakova Gene: ints6 has been classified as Red List (Low Evidence).
Intellectual disability v3.354 CPD Arina Puzriakova Classified gene: CPD as Red List (low evidence)
Intellectual disability v3.354 CPD Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.354 CPD Arina Puzriakova Gene: cpd has been classified as Red List (Low Evidence).
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype with these variants.
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities of it is essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.
Thrombocythaemia v0.8 SH2B3 Catherine Snow Deleted their comment
Thrombocythaemia v0.8 SH2B3 Catherine Snow edited their review of gene: SH2B3: Added comment: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities of it is essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; Changed publications: 20404132, 27716218, 27237057
Thrombocythaemia v0.8 SH2B3 Catherine Snow reviewed gene: SH2B3: Rating: RED; Mode of pathogenicity: None; Publications: 20404132, 27716218; Phenotypes: ; Mode of inheritance: Other
Cytopenia - NOT Fanconi anaemia v1.16 DDX41 Arina Puzriakova Phenotypes for gene: DDX41 were changed from 616871 Susceptibility to myeloid neoplasms to Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to, 616871
Cytopenia - NOT Fanconi anaemia v1.15 DDX41 Arina Puzriakova Classified gene: DDX41 as Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v1.15 DDX41 Arina Puzriakova Added comment: Comment on list classification: The rating of this gene should be re-evaluated by the GMS Haematology Specialist Test Group in context of the recent review by Zornitza Stark (added for-review tag)
Cytopenia - NOT Fanconi anaemia v1.15 DDX41 Arina Puzriakova Gene: ddx41 has been classified as Red List (Low Evidence).
Cytopenia - NOT Fanconi anaemia v1.14 DDX41 Arina Puzriakova Tag for-review tag was added to gene: DDX41.
Cytopenia - NOT Fanconi anaemia v1.14 SRP54 Arina Puzriakova Classified gene: SRP54 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.14 SRP54 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 28 unrelated cases with congenital neutropenia due to variants in SRP54
Cytopenia - NOT Fanconi anaemia v1.14 SRP54 Arina Puzriakova Gene: srp54 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.13 SRP54 Arina Puzriakova Added comment: Comment on publications: Added publications to support association with this phenotype.
Cytopenia - NOT Fanconi anaemia v1.13 SRP54 Arina Puzriakova Publications for gene: SRP54 were set to 28972538
Cytopenia - NOT Fanconi anaemia v1.12 SRP54 Arina Puzriakova Tag for-review tag was added to gene: SRP54.
Cytopenia - NOT Fanconi anaemia v1.12 SRP54 Arina Puzriakova Phenotypes for gene: SRP54 were changed from Syndromic neutropenia with Shwachman-Diamond-like features to Neutropenia, severe congenital, 8, autosomal dominant, 618752
Cytopenia - NOT Fanconi anaemia v1.11 NPM1 Arina Puzriakova Mode of inheritance for gene: NPM1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Unknown
Cytopenia - NOT Fanconi anaemia v1.10 NPM1 Arina Puzriakova Classified gene: NPM1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.10 NPM1 Arina Puzriakova Added comment: Comment on list classification: Rated Amber as additional cases required to corroborate causality and better define the phenotype. Both variants currently classified VUS - no information regarding segregation or zygosity.
Cytopenia - NOT Fanconi anaemia v1.10 NPM1 Arina Puzriakova Gene: npm1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.97 ATP1A2 Rhiannon Mellis reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31608932; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.9 NPM1 Arina Puzriakova reviewed gene: NPM1: Rating: ; Mode of pathogenicity: None; Publications: 31570891; Phenotypes: Dyskeratosis congenita; Mode of inheritance: Unknown
Cytopenia - NOT Fanconi anaemia v1.9 AK2 Arina Puzriakova Phenotypes for gene: AK2 were changed from Reticular dysgenesis, MIM# 267500 to Reticular dysgenesis, 267500
Cytopenia - NOT Fanconi anaemia v1.8 AK2 Arina Puzriakova Added comment: Comment on publications: Added publications to support association with this phenotype.
Cytopenia - NOT Fanconi anaemia v1.8 AK2 Arina Puzriakova Publications for gene: AK2 were set to 19043416
Cytopenia - NOT Fanconi anaemia v1.7 AK2 Arina Puzriakova Classified gene: AK2 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.7 AK2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - >3 unrelated cases with reticular dysgenesis (leukopenia is part of the phenotype) due to biallelic variants in AK2.
Cytopenia - NOT Fanconi anaemia v1.7 AK2 Arina Puzriakova Gene: ak2 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.6 AK2 Arina Puzriakova Tag for-review tag was added to gene: AK2.
Intellectual disability v3.353 KDM6B Arina Puzriakova Classified gene: KDM6B as Amber List (moderate evidence)
Intellectual disability v3.353 KDM6B Arina Puzriakova Added comment: Comment on list classification: Sufficient number of patients to rate this gene GREEN at the next major review - psychomotor delay was consistently reported and was the key indication for clinical investigation in several cases.
Intellectual disability v3.353 KDM6B Arina Puzriakova Gene: kdm6b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.351 KDM6B Arina Puzriakova Publications for gene: KDM6B were set to 21937992
Intellectual disability v3.350 KDM6B Arina Puzriakova Mode of inheritance for gene: KDM6B was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 KDM6B Arina Puzriakova Tag for-review tag was added to gene: KDM6B.
Intellectual disability v3.349 KDM6B Arina Puzriakova reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 HADH Arina Puzriakova Classified gene: HADH as Green List (high evidence)
Intellectual disability v3.349 HADH Arina Puzriakova Added comment: Comment on list classification: As ID is a secondary finding, reported in only a subset of patients, this gene should be downgraded from Green to Amber/Red at the next major review.
Intellectual disability v3.349 HADH Arina Puzriakova Gene: hadh has been classified as Green List (High Evidence).
Intellectual disability v3.348 HADH Arina Puzriakova Phenotypes for gene: HADH were changed from 3-HYDROXYACYL-COENZYME A DEHYDROGENASE DEFICIENCY to Hyperinsulinemic hypoglycemia, familial, 4, 609975; 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530
Intellectual disability v3.347 HADH Arina Puzriakova Tag for-review tag was added to gene: HADH.
Intellectual disability v3.347 HADH Arina Puzriakova reviewed gene: HADH: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 4, 609975, 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.16 SH2B3 Catherine Snow reviewed gene: SH2B3: Rating: RED; Mode of pathogenicity: None; Publications: 23812944, 20843259; Phenotypes: Hereditary Erythrocytosis; Mode of inheritance: Other
Neurodegenerative disorders, adult onset v2.16 SS18L1 Zornitza Stark reviewed gene: SS18L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25888396, 24360741, 23708140, 30976389; Phenotypes: Amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Neurodegenerative disorders, adult onset v2.16 SPG7 Zornitza Stark reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16765570, 19364936; Phenotypes: Spastic paraplegia 7, autosomal recessive MIM#607259; Mode of inheritance: None; Current diagnostic: yes
Neurodegenerative disorders, adult onset v2.16 NEK1 Zornitza Stark reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31768050, 26945885, 27455347, 29929116; Phenotypes: Amyotrophic lateral sclerosis, susceptibility to, 24 MIM#617892; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Neurodegenerative disorders, adult onset v2.16 GLT8D1 Zornitza Stark gene: GLT8D1 was added
gene: GLT8D1 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GLT8D1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GLT8D1 were set to 30811981
Phenotypes for gene: GLT8D1 were set to Amyotrophic lateral sclerosis
Review for gene: GLT8D1 was set to GREEN
gene: GLT8D1 was marked as current diagnostic
Added comment: 14 ALS cases with heterozygous missense (10 cases with p.R92C), and supporting in vitro functional assays and zebrafish model.
Sources: Expert list
Neurodegenerative disorders, adult onset v2.16 GBE1 Zornitza Stark gene: GBE1 was added
gene: GBE1 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 20301758; 26194201
Phenotypes for gene: GBE1 were set to Polyglucosan body disease, adult form MIM#263570
Review for gene: GBE1 was set to GREEN
Added comment: APBD can have upper and lower motor neuron involvement, and at least 5 cases in a cohort of 30 were misdiagnosed with ALS.
Sources: Expert list
Neurodegenerative disorders, adult onset v2.16 ERBB4 Zornitza Stark reviewed gene: ERBB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28889094; Phenotypes: Amyotrophic lateral sclerosis 19, 615515; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v2.16 DNAJB2 Zornitza Stark gene: DNAJB2 was added
gene: DNAJB2 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: DNAJB2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAJB2 were set to Spinal muscular atrophy, distal, autosomal recessive, 5, 614881
Review for gene: DNAJB2 was set to GREEN
Added comment: Young adult onset, progressive neurological disorder, phenotype resembles ALS.
Sources: Expert list
Intellectual disability v3.347 ADGRG6 Arina Puzriakova Phenotypes for gene: ADGRG6 were changed from LETHAL CONGENITAL CONTRACTURE SYNDROME 9 to Lethal congenital contracture syndrome 9, 616503
Intellectual disability v3.346 ADGRG6 Arina Puzriakova Classified gene: ADGRG6 as Red List (low evidence)
Intellectual disability v3.346 ADGRG6 Arina Puzriakova Gene: adgrg6 has been classified as Red List (Low Evidence).
Intellectual disability v3.345 AGL Arina Puzriakova Classified gene: AGL as Red List (low evidence)
Intellectual disability v3.345 AGL Arina Puzriakova Gene: agl has been classified as Red List (Low Evidence).
Intellectual disability v3.344 ALDOB Arina Puzriakova Classified gene: ALDOB as Red List (low evidence)
Intellectual disability v3.344 ALDOB Arina Puzriakova Gene: aldob has been classified as Red List (Low Evidence).
Intellectual disability v3.343 ADCY5 Arina Puzriakova Classified gene: ADCY5 as Red List (low evidence)
Intellectual disability v3.343 ADCY5 Arina Puzriakova Gene: adcy5 has been classified as Red List (Low Evidence).
Intellectual disability v3.342 ABAT Arina Puzriakova Classified gene: ABAT as Amber List (moderate evidence)
Intellectual disability v3.342 ABAT Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team), it has been agreed that this gene should be upgraded from Amber to Green at the next major review.
Intellectual disability v3.342 ABAT Arina Puzriakova Gene: abat has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.341 ABAT Arina Puzriakova Tag for-review tag was added to gene: ABAT.
Intellectual disability v3.341 ABAT Arina Puzriakova reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GABA-transaminase deficiency, 613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.341 ACADSB Arina Puzriakova Phenotypes for gene: ACADSB were changed from to 2-methylbutyrylglycinuria, 610006
Intellectual disability v3.340 ACADSB Arina Puzriakova Mode of inheritance for gene: ACADSB was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.339 ACADSB Arina Puzriakova Classified gene: ACADSB as Amber List (moderate evidence)
Intellectual disability v3.339 ACADSB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as DD has been reported, but only in a subset of symptomatic cases.

Metabolic abnormalities should be a sufficient indication for testing, for which this gene is already rated Green.
Intellectual disability v3.339 ACADSB Arina Puzriakova Gene: acadsb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.338 ACADSB Arina Puzriakova reviewed gene: ACADSB: Rating: ; Mode of pathogenicity: None; Publications: 30730842; Phenotypes: 2-methylbutyrylglycinuria, 610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.22 AHCY Arina Puzriakova Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids) to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Disorders of the metabolism of sulphur amino acids
Undiagnosed metabolic disorders v1.422 AHCY Arina Puzriakova Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids) to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Disorders of the metabolism of sulphur amino acids
Undiagnosed metabolic disorders v1.421 AHCY Arina Puzriakova Publications for gene: AHCY were set to 27604308
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Tag for-review tag was added to gene: AHCY.
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Deleted their comment
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Mode of inheritance for gene: AHCY was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Deleted their comment
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Deleted their comment
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Likely inborn error of metabolism v2.21 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.20 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Likely inborn error of metabolism v2.20 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Likely inborn error of metabolism v2.20 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.20 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Likely inborn error of metabolism v2.20 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder due to variants in AHCY.
Likely inborn error of metabolism v2.20 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.19 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124; 16435181; 16736098; 20852937; 22959829; 26095522; 26527160; 28779239; 30121674; 31957987
Likely inborn error of metabolism v2.19 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124; 16435181; 16736098; 20852937; 22959829; 26095522; 26527160; 28779239; 30121674; 31957987
Likely inborn error of metabolism v2.19 AHCY Arina Puzriakova Publications for gene: AHCY were set to 27604308
Intellectual disability v3.338 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124
Likely inborn error of metabolism v2.18 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Tag for-review tag was added to gene: AHCY.
Likely inborn error of metabolism v2.18 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Likely inborn error of metabolism v2.18 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.23 AHCY Arina Puzriakova Classified gene: AHCY as Green List (high evidence)
Fetal hydrops v1.23 AHCY Arina Puzriakova Added comment: Comment on list classification: Updated rating from Amber to Green based on additional 2020 paper (PMID:31957987) which reports an infant with foetal hydrops - taking the total number of families to three.
Fetal hydrops v1.23 AHCY Arina Puzriakova Gene: ahcy has been classified as Green List (High Evidence).
Fetal hydrops v1.22 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.97 AHCY Arina Puzriakova Publications for gene: AHCY were set to 30121674; 20852937
Fetal anomalies v1.96 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Fetal anomalies v1.96 AHCY Arina Puzriakova Added comment: Comment on list classification: With addition of the recent publication (PMID:31957987) describing a patient with foetal hydrops, among other features, there is now sufficient evidence to rate this gene GREEN at the next major review.
Fetal anomalies v1.96 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.95 AHCY Arina Puzriakova Tag for-review tag was added to gene: AHCY.
Fetal anomalies v1.95 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.337 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Intellectual disability v3.337 AHCY Arina Puzriakova Added comment: Comment on list classification: DD may occasionally be mild, however is an early and consistent finding amongst surviving patients. Inclusion on this panel may benefit detection of patients who would otherwise not be considered for testing via other routes (e.g. where metabolic abnormalities become apparent later).

Therefore, recommending a GREEN rating at the next major review.
Intellectual disability v3.337 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.336 AHCY Arina Puzriakova Tag for-review tag was added to gene: AHCY.
Intellectual disability v3.336 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Intellectual disability v3.336 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Intellectual disability v3.336 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.16 JAK2 Arina Puzriakova Mode of pathogenicity for gene: JAK2 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
Hereditary Erythrocytosis v1.15 JAK2 Arina Puzriakova Mode of inheritance for gene: JAK2 was changed from Unknown to Other
Hereditary Erythrocytosis v1.14 JAK2 Arina Puzriakova reviewed gene: JAK2: Rating: RED; 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: 27389715; Phenotypes: Erythrocytosis, somatic, 133100; Mode of inheritance: Other
Neurodegenerative disorders, adult onset v2.16 SPG21 Zornitza Stark reviewed gene: SPG21: Rating: GREEN; Mode of pathogenicity: None; Publications: 14564668, 24451228, 28752238, 26978163; Phenotypes: Mast syndrome, MIM# 248900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.16 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278385, 21981780, 23269600; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM# 614298; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.94 COL2A1 Eleanor Williams changed review comment from: Associated with Stickler syndrome, type I #108300 (AD) in OMIM.

PMID: 23110709 - Acke et al 2012 - review the literature to give an overview of hearing loss in Stickler syndrome, correlated with the genotype. 313 patients from 102 families were reviewed. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).

PMID: 27408751 - Kondo et al 2016 - report 21 cases (some familial, most sporadic) with COL2A1 variants. 4/21 showed hearing loss.

PMID: 20179744 - Hoornaert et al 2010 - identified 77 different heterozygous COL2A1 mutations in 100 affected individuals out of a group of 188 individuals referred with a potential diagnosis of Stickler syndrome. 30% of COL2A1-variant positive patients had sensorineural hearing loss. However, over a higher percentage (50%) of patients without a COL2A1 mutation have sensorineural hearing loss.; to: Associated with Stickler syndrome, type I #108300 (AD) in OMIM.

PMID: 23110709 - Acke et al 2012 - review the literature to give an overview of hearing loss in Stickler syndrome, correlated with the genotype. 313 patients from 102 families were reviewed. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).

PMID: 27408751 - Kondo et al 2016 - report 21 cases (some familial, most sporadic) with COL2A1 variants. 4/21 (20%) showed hearing loss.

PMID: 20179744 - Hoornaert et al 2010 - identified 77 different heterozygous COL2A1 mutations in 100 affected individuals out of a group of 188 individuals referred with a potential diagnosis of Stickler syndrome. 30% of COL2A1-variant positive patients had sensorineural hearing loss. However, over a higher percentage (50%) of patients without a COL2A1 mutation have sensorineural hearing loss.
Monogenic hearing loss v2.94 COL11A1 Eleanor Williams Classified gene: COL11A1 as Amber List (moderate evidence)
Monogenic hearing loss v2.94 COL11A1 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it has been decided that this gene has sufficient cases with hearing loss to be promoted to green. Therefore this gene should be reviewed at the next GMS update.
Monogenic hearing loss v2.94 COL11A1 Eleanor Williams Gene: col11a1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.93 COL11A1 Eleanor Williams edited their review of gene: COL11A1: Changed rating: GREEN
Intellectual disability v3.336 DDOST Eleanor Williams Classified gene: DDOST as Green List (high evidence)
Intellectual disability v3.336 DDOST Eleanor Williams Added comment: Comment on list classification: Leaving Green until the next major review, but the evidence does not support a green rating; this gene should be demoted to amber or red.
Intellectual disability v3.336 DDOST Eleanor Williams Gene: ddost has been classified as Green List (High Evidence).
Intellectual disability v3.335 DDOST Eleanor Williams Tag for-review tag was added to gene: DDOST.
Intellectual disability v3.335 DDOST Eleanor Williams reviewed gene: DDOST: Rating: AMBER; Mode of pathogenicity: None; Publications: 22305527; Phenotypes: ?Congenital disorder of glycosylation, type Ir, 614507, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thrombocythaemia v0.8 JAK2 Arina Puzriakova Tag somatic tag was added to gene: JAK2.
Thrombocythaemia v0.8 JAK2 Arina Puzriakova edited their review of gene: JAK2: Added comment: Most cases are typically associated with somatic JAK2 variants; however, some hereditary cases (at least 4 families) with different germline heterozygous variants have also been reported.; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 22397670, 23535062, 24381227, 24398328; Changed phenotypes: Thrombocythemia 3, 614521
Thrombocythaemia v0.8 CALR Eleanor Williams changed review comment from: Associated with Myelofibrosis, somatic MIM#254450 and Thrombocythemia, somatic MIM#187950 in OMIM.

PMID: 24325356 - Klampfl et al 2013 - performed WES to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Two patients had somatic deletions in exon 9 of CALR, and the remaining 4 had a recurrent 5-bp insertion. They then screened 382 patients with polycythemia vera, 311 with essential thrombocythemia, and 203 with primary myelofibrosis for alterations in CALR. 78 patients with essential thrombocythemia (25%) and 72 with primary myelofibrosis (35%) had mutations in CALR. All patients with mutated CALR had nonmutated JAK2 and MPL.

PMID: 24325359 - Nangalia et al 2013 - performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers.

PMID: 31778606 - Jan and Choi 2020 - review of molecular basis of myeloproliferative neoplasms - only somatic mutations mentioned, no germline.; to: Associated with Myelofibrosis, somatic MIM#254450 and Thrombocythemia, somatic MIM#187950 in OMIM.

2 papers report somatic mutations. No germline mutations reported to date.

PMID: 24325356 - Klampfl et al 2013 - performed WES to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Two patients had somatic deletions in exon 9 of CALR, and the remaining 4 had a recurrent 5-bp insertion. They then screened 382 patients with polycythemia vera, 311 with essential thrombocythemia, and 203 with primary myelofibrosis for alterations in CALR. 78 patients with essential thrombocythemia (25%) and 72 with primary myelofibrosis (35%) had mutations in CALR. All patients with mutated CALR had nonmutated JAK2 and MPL.

PMID: 24325359 - Nangalia et al 2013 - performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers.

PMID: 31778606 - Jan and Choi 2020 - review of molecular basis of myeloproliferative neoplasms - only somatic mutations mentioned, no germline.
Thrombocythaemia v0.8 CALR Eleanor Williams Phenotypes for gene: CALR were changed from Thrombocythemia, somatic, 187950 to Thrombocythemia, somatic, 187950; Myelofibrosis, somatic, 254450
Thrombocythaemia v0.7 CALR Eleanor Williams Publications for gene: CALR were set to
Thrombocythaemia v0.6 CALR Eleanor Williams reviewed gene: CALR: Rating: AMBER; Mode of pathogenicity: None; Publications: 24325356, 24325359, 31778606; Phenotypes: Myelofibrosis, somatic, 254450, Thrombocythemia, somatic, 187950; Mode of inheritance: Unknown
Intellectual disability v3.335 CYP2U1 Eleanor Williams reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.335 AGPS Arina Puzriakova Phenotypes for gene: AGPS were changed from RHIZOMELIC CHONDRODYSPLASIA PUNCTATA TYPE 3 (RCDP3) to Rhizomelic chondrodysplasia punctata, type 3, 600121
Intellectual disability v3.334 AGPS Arina Puzriakova Publications for gene: AGPS were set to 7807941; 11152660
Intellectual disability v3.333 AGPS Arina Puzriakova Classified gene: AGPS as Green List (high evidence)
Intellectual disability v3.333 AGPS Arina Puzriakova Added comment: Comment on list classification: Though some relevant phenotypic features have been reported, the relationship with ID is not clear from literature. Patients are more likely to be recognised in context of the skeletal phenotype.

Therefore, suggesting a rating downgrade from Green to Amber at the next major review.
Intellectual disability v3.333 AGPS Arina Puzriakova Gene: agps has been classified as Green List (High Evidence).
Intellectual disability v3.332 AGPS Arina Puzriakova Tag for-review tag was added to gene: AGPS.
Intellectual disability v3.332 AGPS Arina Puzriakova reviewed gene: AGPS: Rating: AMBER; Mode of pathogenicity: None; Publications: 7807941, 11152660, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.8 C1orf194 Arina Puzriakova changed review comment from: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; to: PMID: 32592472 (2020) - An additional knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.
Hereditary neuropathy or pain disorder v1.8 C1orf194 Arina Puzriakova edited their review of gene: C1orf194: Added comment: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; Changed publications: 32592472; Changed phenotypes: Charcot-Marie-Tooth
Hereditary neuropathy or pain disorder v1.8 C1orf194 Arina Puzriakova Publications for gene: C1orf194 were set to 31199454
Hereditary neuropathy or pain disorder v1.7 C1orf194 Arina Puzriakova Classified gene: C1orf194 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.7 C1orf194 Arina Puzriakova Added comment: Comment on list classification: This is has been added with an Amber rating, in accordance with the expert review by Zornitza Stark.
Hereditary neuropathy or pain disorder v1.7 C1orf194 Arina Puzriakova Gene: c1orf194 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.332 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v2.154 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.332 UPF3B Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Parkinson Disease and Complex Parkinsonism v1.68 XPR1 Zornitza Stark gene: XPR1 was added
gene: XPR1 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: XPR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: XPR1 were set to 25938945
Phenotypes for gene: XPR1 were set to Basal ganglia calcification, idiopathic, 6, MIM# 616413
Review for gene: XPR1 was set to GREEN
gene: XPR1 was marked as current diagnostic
Added comment: Idiopathic basal ganglia calcification is an autosomal dominant neurodegenerative disorder characterised by adult onset of progressive neuropsychiatric and movement disorders, although some patients remain asymptomatic. Clinical features can include dystonia, parkinsonism, gait abnormalities, psychosis, dementia, and chorea. Brain imaging shows calcifications of the basal ganglia and other brain regions. At least 5 unrelated families reported.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 VPS13C Zornitza Stark gene: VPS13C was added
gene: VPS13C was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: VPS13C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS13C were set to 26942284; 30452786; 28862745
Phenotypes for gene: VPS13C were set to Parkinson disease 23, autosomal recessive, early onset MIM#616840
Review for gene: VPS13C was set to GREEN
gene: VPS13C was marked as current diagnostic
Added comment: >3 individuals with biallelic variants.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 TWNK Zornitza Stark gene: TWNK was added
gene: TWNK was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: TWNK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TWNK were set to 24076137; 22949510; 22580846; 19353676
Phenotypes for gene: TWNK were set to Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 MIM#609286
Review for gene: TWNK was set to GREEN
gene: TWNK was marked as current diagnostic
Added comment: Greater than three cases reported with parkinsonism as a feature of the condition.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 SLC20A2 Zornitza Stark gene: SLC20A2 was added
gene: SLC20A2 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: SLC20A2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC20A2 were set to 22327515; 23334463
Phenotypes for gene: SLC20A2 were set to Basal ganglia calcification, idiopathic, 1, MIM# 213600
Review for gene: SLC20A2 was set to GREEN
gene: SLC20A2 was marked as current diagnostic
Added comment: Over 50 families reported. Affected individuals can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, seizures, and chronic headache.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 PDGFRB Zornitza Stark gene: PDGFRB was added
gene: PDGFRB was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFRB were set to 23255827; 30979360
Phenotypes for gene: PDGFRB were set to Basal ganglia calcification, idiopathic, 4, MIM# 615007
Review for gene: PDGFRB was set to GREEN
gene: PDGFRB was marked as current diagnostic
Added comment: Idiopathic basal ganglia calcification-4 is an autosomal dominant condition characterized by the accumulation of calcium deposits in various brain regions, most commonly in the basal ganglia. Presentation is with parkinsonism and impaired cognitive function.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 PDGFB Zornitza Stark gene: PDGFB was added
gene: PDGFB was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: PDGFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFB were set to 23913003
Phenotypes for gene: PDGFB were set to Basal ganglia calcification, idiopathic, 5, MIM# 615483
Review for gene: PDGFB was set to GREEN
gene: PDGFB was marked as current diagnostic
Added comment: Progressive disorder characterised by neurologic symptoms that are associated with brain calcifications mainly affecting the basal ganglia. Calcifications may also occur in the thalamus, cerebellum, or white matter. Affected individuals have motor symptoms, such as dyskinesias or parkinsonism, headache, cognitive impairment, and psychiatric manifestations, including apathy and depression. More than 10 families reported.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 PDE8B Zornitza Stark gene: PDE8B was added
gene: PDE8B was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: PDE8B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDE8B were set to 20085714; 26769607; 26475694
Phenotypes for gene: PDE8B were set to Striatal degeneration, autosomal dominant, MIM#609161
Review for gene: PDE8B was set to GREEN
Added comment: Movement disorder due to basal ganglia abnormalities, at least three families reported with heterozygous variants in this gene.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.199 NLRP1 Eleanor Williams Phenotypes for gene: NLRP1 were changed from Dyskeratosis, autoimmunity and arthritis; Palmoplantar carcinoma, corneal scarring; Autoinflammatory Disorders; Autoinflammation with arthritis and dyskeratosis to Dyskeratosis, autoimmunity and arthritis; Palmoplantar carcinoma, corneal scarring; Autoinflammatory Disorders; Autoinflammation with arthritis and dyskeratosis, 617388
Primary immunodeficiency or monogenic inflammatory bowel disease v2.198 TREX1 Eleanor Williams Phenotypes for gene: TREX1 were changed from Aicardi-Goutieres syndrome 1, dominant and recessive; Type 1 interferonopathies; Classical AGS, SLE, FCL; Autoinflammatory Disorders to Aicardi-Goutieres syndrome 1, dominant and recessive, 225750; Type 1 interferonopathies; Classical AGS, SLE, FCL; Autoinflammatory Disorders
Primary immunodeficiency or monogenic inflammatory bowel disease v2.197 STK4 Eleanor Williams Phenotypes for gene: STK4 were changed from Hypergammaglobulinaemia, lymphopenia, combined immunodeficiency, congenital heart disease, autoimmunity; T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations; AR hyperimmunoglobulin E syndrome; Combined immunodeficiency; Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease; Immunodeficiencies affecting cellular and humoral immunity to Hypergammaglobulinaemia, lymphopenia, combined immunodeficiency, congenital heart disease, autoimmunity; T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations, 614868; AR hyperimmunoglobulin E syndrome; Combined immunodeficiency; Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.196 DOCK8 Eleanor Williams Phenotypes for gene: DOCK8 were changed from Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections; Combined immunodeficiency; Hyper IgE syndrome (HIES); Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Immunodeficiencies affecting cellular and humoral immunity to Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections; Combined immunodeficiency; Hyper IgE syndrome (HIES); Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.195 MAGT1 Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853 to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 300853; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation
Primary immunodeficiency or monogenic inflammatory bowel disease v2.194 MAGT1 Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853
Intellectual disability v3.332 STAT1 Arina Puzriakova Classified gene: STAT1 as Red List (low evidence)
Intellectual disability v3.332 STAT1 Arina Puzriakova Gene: stat1 has been classified as Red List (Low Evidence).
Intellectual disability v3.331 STAT1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 RASA1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 ABCC6 Arina Puzriakova Classified gene: ABCC6 as Red List (low evidence)
Intellectual disability v3.331 ABCC6 Arina Puzriakova Gene: abcc6 has been classified as Red List (Low Evidence).
Intellectual disability v3.330 ABCC6 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Hereditary Erythrocytosis v1.14 Sarah Leigh Panel types changed to Rare Disease 100K; GMS Rare Disease
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Classified gene: SH2B3 as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Added comment: Comment on list classification: An amber rating has been given to SH2B3, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Gene: sh2b3 has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.12 SH2B3 Sarah Leigh Tag for-review tag was added to gene: SH2B3.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Tag for-review tag was added to gene: JAK2.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Classified gene: JAK2 as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Added comment: Comment on list classification: An amber rating has been given to JAK2, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Gene: jak2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.193 PTEN Arina Puzriakova reviewed gene: PTEN: Rating: ; Mode of pathogenicity: None; Publications: 32588888; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Differences in sex development v2.11 TCF12 Arina Puzriakova changed review comment from: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered.

Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).; to: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered. Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Differences in sex development v2.11 TCF12 Arina Puzriakova Tag watchlist tag was added to gene: TCF12.
Differences in sex development v2.11 TCF12 Arina Puzriakova Classified gene: TCF12 as Amber List (moderate evidence)
Differences in sex development v2.11 TCF12 Arina Puzriakova Added comment: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered.

Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Differences in sex development v2.11 TCF12 Arina Puzriakova Gene: tcf12 has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.10 TCF12 Arina Puzriakova gene: TCF12 was added
gene: TCF12 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: TCF12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TCF12 were set to 32620954
Phenotypes for gene: TCF12 were set to Kallmann syndrome
Review for gene: TCF12 was set to AMBER
Added comment: Note monoallelic variants in this gene are a well-established cause of craniosynostosis.
--------------------------------------------------------------------------------------------------------------------

- PMID: 32620954 (2020) - 13 unrelated kindreds (11 de novo, 1 AD and 1 AR) comprising 14 affected individuals with an anosmic form of isolated GnRH deficiency (IGD) (Kallman syndrome) due to different LoF variants in TCF12.

Clinical manifestation included anosmia and pubertal failure (with reproductive phenotypes such as micropenis, bilateral cryptorchidism, hypospadias). Two unrelated individuals within the cohort additionally exhibited craniosynostosis, and a further two pedigrees had a family history of craniosynostosis (that did not affect the index cases). Multiplex cases typically presented incomplete penetrance.

Loss of tcf12 in a mutant zebrafish model perturbed GnRH neuronal patterning, with concomitant expression attenuation of tcf3a/b and stub1 (latter mutated in other syndromic forms of IGD). Furthermore, restored STUB1 expression rescued loss of tcf12 in vivo.
Sources: Literature
Differences in sex development v2.9 DHX37 Arina Puzriakova Tag for-review tag was added to gene: DHX37.
Differences in sex development v2.9 DHX37 Arina Puzriakova Publications for gene: DHX37 were set to 31337883; 31745530
Differences in sex development v2.8 DHX37 Arina Puzriakova Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46, XY sex reversal 11, 273250
Primary immunodeficiency or monogenic inflammatory bowel disease v2.193 SLC7A7 Arina Puzriakova reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32504080; Phenotypes: Lysinuric protein intolerance, 222700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.20 TNFRSF11A Sarah Leigh Added comment: Comment on mode of inheritance: It is suggested that the mode of inheritance for TNFRSF11A should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review.
Skeletal dysplasia v2.20 TNFRSF11A Sarah Leigh Mode of inheritance for gene: TNFRSF11A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.19 TNFRSF11A Sarah Leigh Tag for-review tag was added to gene: TNFRSF11A.
Parkinson Disease and Complex Parkinsonism v1.68 DNAJC5 Zornitza Stark gene: DNAJC5 was added
gene: DNAJC5 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: DNAJC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNAJC5 were set to 22978711; 21820099; 22235333
Phenotypes for gene: DNAJC5 were set to Ceroid lipofuscinosis, neuronal, 4, Parry type, MIM# 162350
Review for gene: DNAJC5 was set to GREEN
Added comment: Parkinsonism has been described in some individuals with this progressive adult-onset neurodegenerative disorder. The (346_348delCTC) variant is recurrent, without evidence of founder effect.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 DNAJC12 Zornitza Stark gene: DNAJC12 was added
gene: DNAJC12 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: DNAJC12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAJC12 were set to Hyperphenylalaninemia, mild, non-BH4-deficient, MIM#617384
Review for gene: DNAJC12 was set to GREEN
Added comment: Highly variable neurological phenotype, including ID, dystonia, parkinsonism.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 CP Zornitza Stark gene: CP was added
gene: CP was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: CP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CP were set to 28012953
Phenotypes for gene: CP were set to Hemosiderosis, systemic, due to aceruloplasminemia MIM#604290
Review for gene: CP was set to GREEN
Added comment: Parkinsonism is a prominent feature of the condition.
Sources: Expert list
Hereditary spastic paraplegia, adult onset v1.7 WDR45B Zornitza Stark reviewed gene: WDR45B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 TFG Zornitza Stark reviewed gene: TFG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 SPART Zornitza Stark reviewed gene: SPART: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 SLC25A15 Zornitza Stark gene: SLC25A15 was added
gene: SLC25A15 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: SLC25A15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A15 were set to 16376511; 22465082; 28592010
Phenotypes for gene: SLC25A15 were set to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome MIM#238970
Review for gene: SLC25A15 was set to GREEN
Added comment: At least four unrelated cases reported with an adult onset spastic paraparesis as a feature of the condition.
Sources: Expert list
Hereditary spastic paraplegia, adult onset v1.7 SLC1A4 Zornitza Stark reviewed gene: SLC1A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 SLC16A2 Zornitza Stark reviewed gene: SLC16A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 SERAC1 Zornitza Stark reviewed gene: SERAC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 REEP2 Zornitza Stark reviewed gene: REEP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 NKX6-2 Zornitza Stark reviewed gene: NKX6-2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 L1CAM Zornitza Stark reviewed gene: L1CAM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 KIF1C Zornitza Stark reviewed gene: KIF1C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 KDM5C Zornitza Stark reviewed gene: KDM5C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 HACE1 Zornitza Stark reviewed gene: HACE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.24 RAD50 Arina Puzriakova Tag watchlist tag was added to gene: RAD50.
Severe microcephaly v2.24 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, MIM# 613078 to Nijmegen breakage syndrome-like disorder, 613078
Severe microcephaly v2.23 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 19409520; 32212377
Severe microcephaly v2.22 RAD50 Arina Puzriakova Classified gene: RAD50 as Amber List (moderate evidence)
Severe microcephaly v2.22 RAD50 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype (two unrelated cases with severe congenital microcephaly) but additional cases required before inclusion of RAD50 on a diagnostic panel.

Rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Severe microcephaly v2.22 RAD50 Arina Puzriakova Gene: rad50 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype. ; to: Comment on list classification: Note uncertainty regarding ID in the first patient - PMID:1887849 states 'lack of mental retardation', while a later report PMID:19409520 describes 'mild to moderate retardation of psychomotor development'. ID was borderline in the second patient (at age 15 estimated IQ: 85).

Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the phenotype associated with RAD50 variants.
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.; to: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype.
Intellectual disability v3.330 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder,613078; NBSLD to Nijmegen breakage syndrome-like disorder, 613078
Intellectual disability v3.329 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520
Intellectual disability v3.328 RAD50 Arina Puzriakova Classified gene: RAD50 as Red List (low evidence)
Intellectual disability v3.328 RAD50 Arina Puzriakova Added comment: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.
Intellectual disability v3.328 RAD50 Arina Puzriakova Gene: rad50 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Tag watchlist tag was added to gene: DHX16.
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Classified gene: DHX16 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Gene: dhx16 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.153 DHX16 Sarah Leigh gene: DHX16 was added
gene: DHX16 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733
Review for gene: DHX16 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing and seizures were reported in 2 of these cases. No functional studies were reported.
Sources: Literature
Osteopetrosis v1.2 Sarah Leigh Panel version has been signed off
Intellectual disability v3.327 WASHC4 Arina Puzriakova Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, MIM #615817 to Mental retardation, autosomal recessive 43, 615817
Intellectual disability v3.326 WASHC4 Arina Puzriakova Classified gene: WASHC4 as Amber List (moderate evidence)
Intellectual disability v3.326 WASHC4 Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of mild/borderline ID in 2/3 families. Additional cases with a more significant manifestation of ID required before inclusion of WASHC4 on a diagnostic panel.
Intellectual disability v3.326 WASHC4 Arina Puzriakova Gene: washc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.325 WASHC4 Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteopetrosis v1.0 Sarah Leigh promoted panel to version 1.0
Intellectual disability v3.325 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from SPINOCEREBELLAR ATAXIA 28 to Spastic ataxia 5, autosomal recessive, 614487
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Classified gene: AFG3L2 as Green List (high evidence)
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Added comment: Comment on list classification: This gene should be downgraded from Green to Red at the next major review, in accordance with the review by Zornitza Stark.
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Gene: afg3l2 has been classified as Green List (High Evidence).
Intellectual disability v3.323 AFG3L2 Arina Puzriakova Publications for gene: AFG3L2 were set to 22022284
Intellectual disability v3.322 AFG3L2 Arina Puzriakova Tag for-review tag was added to gene: AFG3L2.
Intellectual disability v3.322 RASA1 Arina Puzriakova Classified gene: RASA1 as Red List (low evidence)
Intellectual disability v3.322 RASA1 Arina Puzriakova Gene: rasa1 has been classified as Red List (Low Evidence).
Structural eye disease v1.11 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: The eye disorders relevant to this panel are associated with Osteoporosis-pseudoglioma syndrome 259770, which is biallelic. Exudative vitreoretinopathy 4, 601813, which can be biallelic or monoallelic is relavant to the Retinal disorders panel, where both biallelic and monoallelic variants are considered (https://panelapp.genomicsengland.co.uk/panels/307/gene/LRP5/#!review).
Structural eye disease v1.11 LRP5 Sarah Leigh Mode of inheritance for gene: LRP5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.10 LRP5 Sarah Leigh Publications for gene: LRP5 were set to 29131652, 28111184, 20034086
Intellectual disability v3.321 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: Other phenotypes associated with LRP5 variants (https://www.omim.org/entry/603506?search=LRP5&highlight=lrp5#geneMap) have monoallelic inheritance, however, these phenotypes are not relevant for this panel as ID has not been reported.
Intellectual disability v3.321 LRP5 Sarah Leigh Mode of inheritance for gene: LRP5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.320 WDFY3 Arina Puzriakova Classified gene: WDFY3 as Amber List (moderate evidence)
Intellectual disability v3.320 WDFY3 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of cases with moderate ID to meet the threshold for inclusion on a diagnostic ID panel. Furthermore, ID is currently the most applicable clinical indication for detecting these cases using PanelApp panels.

Therefore, recommending a rating upgrade from Amber to Green at the next major review.
Intellectual disability v3.320 WDFY3 Arina Puzriakova Gene: wdfy3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.319 WDFY3 Arina Puzriakova Tag for-review tag was added to gene: WDFY3.
Osteopetrosis v0.10 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts (email 16/09/20200). They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).; to: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts (email 16/09/20200). They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallelic osteopetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identified by RNA-seq analysis of Xanthogranulomatous epithelial tumour in a patient with osteopetrosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).; to: Comment on list classification: Published reports include three variants in two cases of biallelic osteopetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identified by RNA-seq analysis of Xanthogranulomatous epithelial tumour in a patient with osteopetrosis, however, the zygosity of this variant was not reported (PMID 32415263).
Intellectual disability v3.319 TRAK1 Arina Puzriakova Phenotypes for gene: TRAK1 were changed from to Epileptic encephalopathy, early infantile, 68, 618201
Intellectual disability v3.318 TRAK1 Arina Puzriakova Publications for gene: TRAK1 were set to
Intellectual disability v3.317 TRAK1 Arina Puzriakova Mode of inheritance for gene: TRAK1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.316 TRAK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).; to: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, TRAK1 currently does not meet the threshold to say that variants cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Classified gene: TRAK1 as Amber List (moderate evidence)
Intellectual disability v3.316 TRAK1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Gene: trak1 has been classified as Amber List (Moderate Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.99 DIS3L2 Ivone Leong Classified gene: DIS3L2 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.99 DIS3L2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence for this gene to be rated Green. It is also Green on Tumour predisposition - childhood onset (Version 2.13), Childhood solid tumours cancer susceptibility (Version 1.13), Skeletal dysplasia (Version 2.19), Fetal anomalies (Version 1.95), DDG2P (Version 2.9), Intellectual disability (Version 3.315) and Severe Paediatric Disorders (Version 1.11).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.99 DIS3L2 Ivone Leong Gene: dis3l2 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.98 DIS3L2 Ivone Leong Phenotypes for gene: DIS3L2 were changed from Perlman syndrome, MIM# 267000 to Perlman syndrome, 267000
Intellectual disability v3.315 TRAK1 Arina Puzriakova reviewed gene: TRAK1: Rating: ; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.8 NSUN3 Zornitza Stark reviewed gene: NSUN3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27356879, 32488845; Phenotypes: Combined oxidative phosphorylation deficiency 48, MIM# 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.315 SLC12A2 Konstantinos Varvagiannis reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.93 FOXI1 Eleanor Williams Tag for-review tag was added to gene: FOXI1.
Monogenic hearing loss v2.93 FOXI1 Eleanor Williams Classified gene: FOXI1 as Amber List (moderate evidence)
Monogenic hearing loss v2.93 FOXI1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. There are 2 homozygous and several heterozygous cases reported and it could be promoted to green after GMS review. Although most cases are syndromic hearing loss is a major feature. There is some debate about the whether it is homozygous only or also heterozygously inherited, however the homozygous cases are more convincing.
Monogenic hearing loss v2.93 FOXI1 Eleanor Williams Gene: foxi1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.92 FOXI1 Eleanor Williams edited their review of gene: FOXI1: Changed rating: GREEN
Monogenic hearing loss v2.92 FOXI1 Eleanor Williams reviewed gene: FOXI1: Rating: ; Mode of pathogenicity: None; Publications: 17503324, 29242249, 12642503, 9843211; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.92 FOXF2 Eleanor Williams Classified gene: FOXF2 as Amber List (moderate evidence)
Monogenic hearing loss v2.92 FOXF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. 1 case reported with segregation of the variants, plus some mouse model evidence.
Monogenic hearing loss v2.92 FOXF2 Eleanor Williams Gene: foxf2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.91 FOXF2 Eleanor Williams reviewed gene: FOXF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30561639, 22022403; Phenotypes: sensorineural hearing loss (SNHL); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.91 ESRP1 Eleanor Williams Classified gene: ESRP1 as Amber List (moderate evidence)
Monogenic hearing loss v2.91 ESRP1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. 1 case with segregation data reported, plus mouse knockout model.
Monogenic hearing loss v2.91 ESRP1 Eleanor Williams Gene: esrp1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.90 ESRP1 Eleanor Williams Phenotypes for gene: ESRP1 were changed from Deafness, autosomal recessive 109, MIM# 618013 to Deafness, autosomal recessive 109, 618013
Monogenic hearing loss v2.89 ESRP1 Eleanor Williams reviewed gene: ESRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29107558; Phenotypes: ?Deafness, autosomal recessive 109, 618013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v1.7 GJA1 Zornitza Stark gene: GJA1 was added
gene: GJA1 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: GJA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GJA1 were set to 31023660
Phenotypes for gene: GJA1 were set to Hereditary spastic paraplegia; Oculodentodigital dysplasia, MIM#164200
Review for gene: GJA1 was set to GREEN
gene: GJA1 was marked as current diagnostic
Added comment: 8 individuals from 5 families with oculodentodigital dysplasia presenting in adulthood with onset of spastic paraplegia and white matter changes on imaging.
Sources: Expert list
Hereditary spastic paraplegia, adult onset v1.7 GBE1 Zornitza Stark gene: GBE1 was added
gene: GBE1 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 23034915
Phenotypes for gene: GBE1 were set to Polyglucosan body disease, adult form MIM#263570
Review for gene: GBE1 was set to GREEN
gene: GBE1 was marked as current diagnostic
Added comment: Spastic paraplegia is a reported as a prominent feature of the condition in 45/50 cases diagnosed with adult polyglucosan body disease.
Sources: Expert list
Hereditary spastic paraplegia, adult onset v1.7 GALC Zornitza Stark gene: GALC was added
gene: GALC was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: GALC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALC were set to 9272171; 11971051; 22959700; 26396125; 26915362; 28547031; 31185936; 32064984
Phenotypes for gene: GALC were set to Krabbe disease MIM#245200
Review for gene: GALC was set to GREEN
gene: GALC was marked as current diagnostic
Added comment: Adult onset spastic paraplegia is reported as a feature of the condition in greater than 3 cases.
Sources: Expert list
Hereditary spastic paraplegia, adult onset v1.7 FBXO7 Zornitza Stark gene: FBXO7 was added
gene: FBXO7 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: FBXO7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO7 were set to 18513678; 19038853
Phenotypes for gene: FBXO7 were set to Parkinson disease 15, autosomal recessive MIM#260300
Review for gene: FBXO7 was set to GREEN
gene: FBXO7 was marked as current diagnostic
Added comment: Lower limb spasticity reported in at least three families.
Sources: Expert list
Hereditary spastic paraplegia, adult onset v1.7 FARS2 Zornitza Stark reviewed gene: FARS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 ERLIN1 Zornitza Stark reviewed gene: ERLIN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 ENTPD1 Zornitza Stark reviewed gene: ENTPD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 CPT1C Zornitza Stark Deleted their review
Hereditary spastic paraplegia, adult onset v1.7 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23973755; Phenotypes: Spastic paraplegia 73, autosomal dominant, 616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.89 COL11A1 Eleanor Williams Tag for-review tag was added to gene: COL11A1.
Monogenic hearing loss v2.89 COL2A1 Eleanor Williams Classified gene: COL2A1 as Amber List (moderate evidence)
Monogenic hearing loss v2.89 COL2A1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Should be reviewed by the GMS as to whether it is appropriate to make green.
Monogenic hearing loss v2.89 COL2A1 Eleanor Williams Gene: col2a1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.88 COL2A1 Eleanor Williams Mode of inheritance for gene: COL2A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.87 COL2A1 Eleanor Williams Publications for gene: COL2A1 were set to
Monogenic hearing loss v2.86 COL2A1 Eleanor Williams Phenotypes for gene: COL2A1 were changed from Stickler syndrome, type I, 108300Kniest dysplasia, 156550Achondrogenesis, type II or hypochondrogenesis, 200610SED congenita, 183900SMED Strudwick type, 184250Epiphyseal dysplasia, multiple, with myopia and deafness, 132450Spondyloperipheral dysplasia, 271700SED, Namaqualand typeOsteoarthritis with mild chondrodysplasia, 604864Vitreoretinopathy with phalangeal epiphyseal dysplasiaPlatyspondylic skeletal dysplasia, Torrance type, 151210Otospondylomegaepiphyseal dysplasia, 215150Avascular necrosis of the femoral head, 608805Legg-Calve-Perthes disease, 150600Stickler sydrome, type I, nonsyndromic ocular, 609508Czech dysplasia, 609162; ticklersyndrome,typeI,108300Kniestdysplasia,156550Achondrogenesis,typeIIorhypochondrogenesis,200610SEDcongenita,183900 to Stickler syndrome, type I, 108300
Monogenic hearing loss v2.85 COL9A2 Eleanor Williams Tag for-review tag was added to gene: COL9A2.
Hereditary spastic paraplegia, adult onset v1.7 C12orf65 Zornitza Stark reviewed gene: C12orf65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 ARG1 Zornitza Stark reviewed gene: ARG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 AP4E1 Zornitza Stark reviewed gene: AP4E1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.85 COL9A3 Eleanor Williams Tag for-review tag was added to gene: COL9A3.
Hereditary spastic paraplegia, adult onset v1.7 AP4B1 Zornitza Stark reviewed gene: AP4B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.85 COL9A3 Eleanor Williams Classified gene: COL9A3 as Amber List (moderate evidence)
Monogenic hearing loss v2.85 COL9A3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. 2 cases of a Stickler syndrome phenotype reported, which includes hearing loss.
Monogenic hearing loss v2.85 COL9A3 Eleanor Williams Gene: col9a3 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, adult onset v1.7 ALS2 Zornitza Stark reviewed gene: ALS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.84 COL9A3 Eleanor Williams Phenotypes for gene: COL9A3 were changed from to Stickler syndrome
Monogenic hearing loss v2.83 COL9A3 Eleanor Williams Publications for gene: COL9A3 were set to
Monogenic hearing loss v2.82 COL9A3 Eleanor Williams Mode of inheritance for gene: COL9A3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.81 COL9A3 Eleanor Williams edited their review of gene: COL9A3: Changed rating: AMBER; Changed publications: 31090205, 24273071; Changed phenotypes: Stickler syndrome; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.81 COL9A3 Eleanor Williams commented on gene: COL9A3
Hereditary spastic paraplegia, adult onset v1.7 AIMP1 Zornitza Stark reviewed gene: AIMP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia, adult onset v1.7 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive 614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.15 WASHC5 Zornitza Stark reviewed gene: WASHC5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 8, autosomal dominant, 603563; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.81 COL9A1 Eleanor Williams changed review comment from: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 2 distantly related Moroccan families with frameshift COL9A1 variants and Stickler syndrome. 2 cases of non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.; to: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 1 unknown ethnicity family with R507X variants and 2 distantly related Moroccan families with R295X COL9A1 variants and Stickler syndrome. 2 cases of non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.

PMID: 31090205 - Nixon et al 2019 - report 1 case of a 6 year old child with a homozygous nonsense variant in COL9A1 (c.1519C>T, p.(Arg507Ter)) and a diagnosis of Stickler syndrome. This variant has been described previously (Nikopoulos et al., 2011). The child had high‐frequency sensorineural hearing loss.
Monogenic hearing loss v2.81 COL9A2 Eleanor Williams Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2, 600204{Intervertebral disc disease, susceptibility to}, 603932Stickler syndrome, type V, 614284; Epiphysealdysplasia,multiple,2,600204{Intervertebraldiscdisease,susceptibilityto},603932Sticklersyndrome,typeV,614284 to ?Stickler syndrome, type V, 614284
Monogenic hearing loss v2.80 COL9A2 Eleanor Williams Publications for gene: COL9A2 were set to
Monogenic hearing loss v2.79 COL9A2 Eleanor Williams Added comment: Comment on mode of inheritance: 3 reported cases are all homozygous
Monogenic hearing loss v2.79 COL9A2 Eleanor Williams Mode of inheritance for gene: COL9A2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.78 COL9A2 Eleanor Williams Classified gene: COL9A2 as Amber List (moderate evidence)
Monogenic hearing loss v2.78 COL9A2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber, but sufficient cases to rate green following GMS review of appropriateness of this gene for a non-syndromic hearing loss panel.
Monogenic hearing loss v2.78 COL9A2 Eleanor Williams Gene: col9a2 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.15 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Monogenic hearing loss v2.77 COL9A2 Eleanor Williams reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671392, 31090205; Phenotypes: ?Stickler syndrome, type V, 614284; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.77 COL11A1 Eleanor Williams commented on gene: COL11A1: PMID: 23967202 - Miyagawa et al 2013 - report 3 missense variants in Japanese hearing loss patients through targeted exome sequencing. 1 familial case shown with two affected siblings. They suggest the inheritance is autosomal dominant.
Monogenic hearing loss v2.77 COL9A1 Eleanor Williams Tag for-review tag was added to gene: COL9A1.
Monogenic hearing loss v2.77 COL9A1 Eleanor Williams Classified gene: COL9A1 as Amber List (moderate evidence)
Monogenic hearing loss v2.77 COL9A1 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber, but maybe appropriate for green rating following GMS review.
Monogenic hearing loss v2.77 COL9A1 Eleanor Williams Gene: col9a1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.76 COL9A1 Eleanor Williams Phenotypes for gene: COL9A1 were changed from Epiphyseal dysplasia, multiple, 6, 614135Stickler syndrome, type IV, 614134; Epiphysealdysplasia,multiple,6,614135Sticklersyndrome,typeIV,614134 to Stickler syndrome, type IV, 614134; hearing loss
Monogenic hearing loss v2.75 COL9A1 Eleanor Williams Publications for gene: COL9A1 were set to
Hereditary spastic paraplegia, childhood onset v2.15 RNF170 Zornitza Stark gene: RNF170 was added
gene: RNF170 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: RNF170 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF170 were set to 31636353
Phenotypes for gene: RNF170 were set to Hereditary spastic paraplegia
Review for gene: RNF170 was set to GREEN
Added comment: Four families reported with a complicated HSP phenotype.
Sources: Expert list
Monogenic hearing loss v2.74 COL9A1 Eleanor Williams changed review comment from: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 2 distantly related Moroccan families with frameshift COL9A1 variants and Stickler syndrome. 2 cases on non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.; to: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 2 distantly related Moroccan families with frameshift COL9A1 variants and Stickler syndrome. 2 cases of non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.
Monogenic hearing loss v2.74 COL9A1 Eleanor Williams reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16909383, 21421862, 23967202, 31315069; Phenotypes: Stickler syndrome, type IV, 614134, hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.15 RNASEH2B Zornitza Stark reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29691679, 30223285, 29239743, 28762473; Phenotypes: Aicardi-Goutieres syndrome 2, MIM# 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia, childhood onset v2.15 RAB3GAP2 Zornitza Stark reviewed gene: RAB3GAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32376645; Phenotypes: Martsolf syndrome, MIM# 212720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia, childhood onset v2.15 MAPK8IP3 Zornitza Stark gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30612693; 30945334
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities, MIM# 618443
Review for gene: MAPK8IP3 was set to GREEN
gene: MAPK8IP3 was marked as current diagnostic
Added comment: PMID: 30612693 - 13 unrelated children patients with de novo variants, supported by functional studies. Patients have developmental delay (13/13), spasticity (4/13), ataxia (2/13), unstable gait (1/13), microcephaly (3/13), generalized seizures (3/13). No signs of regression, but cerebellar atrophy (3/12), thin corpus callosum (4/10), perisylvian polymicrogyria (2/12), white matter loss (4/12) was noted

PMID: 30945334 - 5 child patients (4 families) with spastic diplegia (4/5), ID (5/5), epilepsy (2/5) and cerebellar atrophy (5/5), corpus callosum hypoplasia (5/5).

Overall 8/18 individuals with spasticity.
Sources: Expert list
Hereditary spastic paraplegia, childhood onset v2.15 MAG Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia, childhood onset v2.15 KLC2 Zornitza Stark gene: KLC2 was added
gene: KLC2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KLC2 were set to Spastic paraplegia, optic atrophy, and neuropathy, MIM#609541
Review for gene: KLC2 was set to GREEN
gene: KLC2 was marked as current diagnostic
Added comment: In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene was identified. Gene is associated with disease, however deletion may not be tractable by all testing methods and/or this association may be better defined as a CNV.
Sources: Expert list
Hereditary spastic paraplegia, childhood onset v2.15 IFIH1 Zornitza Stark gene: IFIH1 was added
gene: IFIH1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFIH1 were set to 25243380; 31427910; 24686847; 24995871
Phenotypes for gene: IFIH1 were set to Aicardi-Goutieres syndrome 7 MIM#615846
Review for gene: IFIH1 was set to GREEN
Added comment: At least four cases reported with spastic paraparesis as a feature of the condition.
Sources: Expert list
Hereditary spastic paraplegia, childhood onset v2.15 IBA57 Zornitza Stark reviewed gene: IBA57: Rating: GREEN; Mode of pathogenicity: None; Publications: 25609768, 30258207; Phenotypes: Spastic paraplegia 74, autosomal recessive MIM#616451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia, childhood onset v2.15 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233, Spastic paraplegia 13, autosomal dominant, MIM# 605280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia, childhood onset v2.15 GPT2 Zornitza Stark gene: GPT2 was added
gene: GPT2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 29882329; 31471722; 27601654
Phenotypes for gene: GPT2 were set to Mental retardation, autosomal recessive 49 MIM#616281
Review for gene: GPT2 was set to GREEN
gene: GPT2 was marked as current diagnostic
Added comment: Paediatric onset spastic paraglegia is a prominent feature of the condition, >3 unrelated families reported.
Sources: Expert list
Hereditary spastic paraplegia, childhood onset v2.15 GLRX5 Zornitza Stark gene: GLRX5 was added
gene: GLRX5 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: GLRX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLRX5 were set to 24334290; 30770271
Phenotypes for gene: GLRX5 were set to Spasticity, childhood-onset, with hyperglycinemia 616859
Review for gene: GLRX5 was set to GREEN
gene: GLRX5 was marked as current diagnostic
Added comment: Spasticity is a key presenting feature of this condition.
Sources: Expert list
Hereditary spastic paraplegia, childhood onset v2.15 EXOSC3 Zornitza Stark gene: EXOSC3 was added
gene: EXOSC3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: EXOSC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC3 were set to 25149867; 23975261
Phenotypes for gene: EXOSC3 were set to Complicated hereditary spastic paraplegia
Review for gene: EXOSC3 was set to AMBER
Added comment: Two families with a complicated HSP phenotype.
Sources: Expert list
Hereditary spastic paraplegia, childhood onset v2.15 ELOVL1 Zornitza Stark gene: ELOVL1 was added
gene: ELOVL1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 29496980; 32123819; 30487246
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527
Review for gene: ELOVL1 was set to GREEN
gene: ELOVL1 was marked as current diagnostic
Added comment: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity. Affected individuals have mild facial dysmorphism.

Same two individuals reported in two publications. Both had the same variant, p.S165F, which arose de novo, suggesting the residue is important in pathogenesis. Mouse model.
Sources: Expert list
Intellectual disability v3.315 ZMYM2 Konstantinos Varvagiannis gene: ZMYM2 was added
gene: ZMYM2 was added to Intellectual disability. Sources: Literature
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
Review for gene: ZMYM2 was set to AMBER
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Differences in sex development v2.7 DHX37 Arina Puzriakova Classified gene: DHX37 as Amber List (moderate evidence)
Differences in sex development v2.7 DHX37 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review.
Differences in sex development v2.7 DHX37 Arina Puzriakova Gene: dhx37 has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.6 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 31287541, 31745530, 31337883; Phenotypes: 46, XY sex reversal 11, 273250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.315 DHX37 Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene (albeit association with monoallelic variants in 2 cases warrants further investigation).
Intellectual disability v3.315 DHX37 Arina Puzriakova Classified gene: DHX37 as Amber List (moderate evidence)
Intellectual disability v3.315 DHX37 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.
Intellectual disability v3.315 DHX37 Arina Puzriakova Gene: dhx37 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.314 DHX37 Arina Puzriakova Tag for-review tag was added to gene: DHX37.
Intellectual disability v3.314 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877; Phenotypes: Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, 618731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.193 TLR7 Arina Puzriakova Classified gene: TLR7 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.193 TLR7 Arina Puzriakova Added comment: Comment on list classification: Phenotype is more relevant to a severe COVID-19 clinical course - this gene is already Green on the COVID-19 research panel (Version 1.69).
Therefore, rating Amber, but this can be reviewed if new evidence emerges.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.193 TLR7 Arina Puzriakova Gene: tlr7 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.9 FNIP1 Arina Puzriakova Tag for-review tag was added to gene: FNIP1.
Paediatric or syndromic cardiomyopathy v1.9 FNIP1 Arina Puzriakova Classified gene: FNIP1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.9 FNIP1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 5 unrelated cases with hypertrophic cardiomyopathy associated with biallelic FNIP1 variants, as well as supportive functional data and animal model.
Paediatric or syndromic cardiomyopathy v1.9 FNIP1 Arina Puzriakova Gene: fnip1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.8 FNIP1 Arina Puzriakova gene: FNIP1 was added
gene: FNIP1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FNIP1 were set to 32181500; 32905580
Phenotypes for gene: FNIP1 were set to Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia
Review for gene: FNIP1 was set to GREEN
Added comment: - PMID: 32181500 (2020) - Three patients from two independent consanguineous families with homozygous variants (c.3353G>A, p.Ser1118Asn and c.1289delA, p.His430Profs7*) in the FNIP1 gene. Both variants segregated with the disease phenotype in each family. Clinically, patients presented with combined immunodeficiency, cardiac findings (hypertrophic cardiomyopathy, Wolff‐Parkinson‐White syndrome), and myopathy of skeletal muscles with motor DD. Authors note phenotypic overlap with the murine model of FNIP1 deficiency, but no functional analyses of the variants or patient cells were performed.

- PMID: 32905580 (2020) - Three cases from unrelated families, all harbouring novel biallelic variants in FNIP1. Clinical manifestations in all patients include hypertrophic cardiomyopathy, severe and/or recurrent infections, absent circulating B-cells, and agammaglobulinemia; as well as either severe or intermittent neutropenia in two cases. Functional studies showed impairment of B-cell metabolism, including disruptions to mitochondrial numbers/activity and the PI3K/AKT pathway.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.192 FNIP1 Arina Puzriakova Publications for gene: FNIP1 were set to 32905580
Primary immunodeficiency or monogenic inflammatory bowel disease v2.191 FNIP1 Arina Puzriakova Classified gene: FNIP1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.191 FNIP1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 5 unrelated cases with immunodeficiency associated with biallelic FNIP1 variants, as well as supportive functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.191 FNIP1 Arina Puzriakova Gene: fnip1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.190 FNIP1 Arina Puzriakova Tag for-review tag was added to gene: FNIP1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.190 FNIP1 Arina Puzriakova reviewed gene: FNIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32181500, 32905580; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.190 TOM1 Arina Puzriakova Classified gene: TOM1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.190 TOM1 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but currently only a single family reported. Therefore, rating Red awaiting additional cases/clinical evidence to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.190 TOM1 Arina Puzriakova Gene: tom1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.189 TOM1 Arina Puzriakova reviewed gene: TOM1: Rating: ; Mode of pathogenicity: None; Publications: 31263572; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.189 TNFSF13 Arina Puzriakova Classified gene: TNFSF13 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.189 TNFSF13 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but currently only a single case. Therefore, rating Red awaiting additional cases/clinical evidence to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.189 TNFSF13 Arina Puzriakova Gene: tnfsf13 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.188 TNFSF13 Arina Puzriakova reviewed gene: TNFSF13: Rating: ; Mode of pathogenicity: None; Publications: 32298700; Phenotypes: Common variable immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.15 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: RED; Mode of pathogenicity: None; Publications: 25751282; Phenotypes: Spastic paraplegia 73, autosomal dominant, 616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.152 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to AMBER
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability v3.314 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to GREEN
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability v3.314 SPTBN4 Konstantinos Varvagiannis edited their review of gene: SPTBN4: Added comment: ** Consider also the GeneReview on this disorder - PMID : 32672909; Changed publications: 28540413, 28940097, 29861105, 31230720, 31857255, 32672909
Primary immunodeficiency or monogenic inflammatory bowel disease v2.188 TET2 Arina Puzriakova changed review comment from: Comment on list classification: Additional cases required before inclusion of this gene on a diagnostic panel.

Rating Amber in anticipation of further publications/clinical evidence.; to: Comment on list classification: Additional cases required before inclusion of this gene on a diagnostic panel. Rating Amber in anticipation of further publications/clinical evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.188 TET2 Arina Puzriakova Classified gene: TET2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.188 TET2 Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion of this gene on a diagnostic panel.

Rating Amber in anticipation of further publications/clinical evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.188 TET2 Arina Puzriakova Gene: tet2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 TET2 Arina Puzriakova changed review comment from: PMID: 32518946 (2020) - Three cases from two unrelated consanguineous families with immunodeficiency and lymphoproliferative disease, associated with homozygous variants (c.4145A>G, p.H1382R and c.4894C>T,
p.Q1632*) in the TET2 gene. Molecular studies showed that the variants result in altered DNA methylation and B-cell maturation, as well as skewed T-cell differentiation and hematopoiesis.; to: PMID: 32518946 (2020) - Three cases from two unrelated consanguineous families with immunodeficiency and lymphoproliferative disease, associated with homozygous variants (c.4145A>G, p.H1382R and c.4894C>T, p.Q1632*) in the TET2 gene. Molecular studies showed that the variants result in altered DNA methylation and B-cell maturation, as well as skewed T-cell differentiation and hematopoiesis.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 TET2 Arina Puzriakova reviewed gene: TET2: Rating: ; Mode of pathogenicity: None; Publications: 32518946; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 MCM10 Arina Puzriakova Classified gene: MCM10 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 MCM10 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 MCM10 Arina Puzriakova Gene: mcm10 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.186 MAPK8 Arina Puzriakova Classified gene: MAPK8 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.186 MAPK8 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.186 MAPK8 Arina Puzriakova Gene: mapk8 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.185 MAPK8 Arina Puzriakova reviewed gene: MAPK8: Rating: ; Mode of pathogenicity: None; Publications: 31784499; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Osteopetrosis v0.10 Sarah Leigh removed gene:IKBKG from the panel
Osteopetrosis v0.9 IKBKG Sarah Leigh changed review comment from: GMS specialist disease group expert has requested that this gene should be deleted from this panel (email 16/09/2020). This is due to the issue of the presence of a pseudogene.; to: GMS specialist disease group experts has requested that this gene should be deleted from this panel (email 16/09/2020). This is due to the issue of the presence of a pseudogene.
Osteopetrosis v0.9 IKBKG Sarah Leigh commented on gene: IKBKG
Primary immunodeficiency or monogenic inflammatory bowel disease v2.185 CTNNBL1 Arina Puzriakova Classified gene: CTNNBL1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.185 CTNNBL1 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.185 CTNNBL1 Arina Puzriakova Gene: ctnnbl1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 CTNNBL1 Arina Puzriakova reviewed gene: CTNNBL1: Rating: ; Mode of pathogenicity: None; Publications: 32484799; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Tag watchlist tag was added to gene: PLEKHM1.
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Tag watchlist tag was added to gene: PLEKHM1.
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Classified gene: PLEKHM1 as Amber List (moderate evidence)
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Added comment: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Gene: plekhm1 has been classified as Amber List (Moderate Evidence).
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts. They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity was not reported (PMID 32415263).; to: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts (email 16/09/20200). They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Classified gene: PLEKHM1 as Amber List (moderate evidence)
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Added comment: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts. They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity was not reported (PMID 32415263).
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Gene: plekhm1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.18 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159; 28290981
Osteopetrosis v0.8 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to
Osteopetrosis v0.7 TCIRG1 Sarah Leigh Publications for gene: TCIRG1 were set to
Haematological malignancies cancer susceptibility v2.5 TSR2 Arina Puzriakova changed review comment from: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red/Amber.; to: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red.
Skeletal dysplasia v2.17 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159
Haematological malignancies cancer susceptibility v2.5 TSR2 Arina Puzriakova Phenotypes for gene: TSR2 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML, Leukemia risk not well defined; Osteosarcoma, soft tissue sarcomas to Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, 300946
Haematological malignancies cancer susceptibility v2.4 TSR2 Arina Puzriakova Classified gene: TSR2 as Green List (high evidence)
Haematological malignancies cancer susceptibility v2.4 TSR2 Arina Puzriakova Added comment: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red/Amber.
Haematological malignancies cancer susceptibility v2.4 TSR2 Arina Puzriakova Gene: tsr2 has been classified as Green List (High Evidence).
Skeletal dysplasia v2.16 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709
Bleeding and platelet disorders v1.9 IKZF5 Arina Puzriakova Publications for gene: IKZF5 were set to 1217188
Bleeding and platelet disorders v1.8 IKZF5 Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 7 unrelated families with thrombocytopenia associated with different missense variants in the IKZF5 gene.
Bleeding and platelet disorders v1.8 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from 130050 Ehlers-Danlos syndrome, vascular type to Ehlers-Danlos syndrome, vascular type, 130050
Bleeding and platelet disorders v1.7 COL3A1 Arina Puzriakova reviewed gene: COL3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29050841, 27259332, 31391389, 25940258, 20720362; Phenotypes: Ehlers-Danlos syndrome, vascular type, 130050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v1.69 DOCK8 Sarah Leigh Phenotypes for gene: DOCK8 were changed from Combined immunodeficiency; Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper IgE syndrome (HIES); Immunodeficiencies affecting cellular and humoral immunity; Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections to Hyper-IgE recurrent infection syndrome, autosomal recessive 243700; Combined immunodeficiency; Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper IgE syndrome (HIES); Immunodeficiencies affecting cellular and humoral immunity; Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections
Bleeding and platelet disorders v1.7 CHST14 Arina Puzriakova Phenotypes for gene: CHST14 were changed from 601776 Ehlers-Danlos syndrome, musculocontractural type 1 to Ehlers-Danlos syndrome, musculocontractural type 1, 601776
Bleeding and platelet disorders v1.6 CHST14 Arina Puzriakova Tag for-review tag was added to gene: CHST14.
Bleeding and platelet disorders v1.6 CHST14 Arina Puzriakova reviewed gene: CHST14: Rating: GREEN; Mode of pathogenicity: None; Publications: 20004762, 26373698, 26646600; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1, 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.15 ATAD3A Zornitza Stark reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28158749, 27640307; Phenotypes: Harel-Yoon syndrome, MIM# 617183; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia, childhood onset v2.15 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26085577; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.15 ALDH3A2 Zornitza Stark gene: ALDH3A2 was added
gene: ALDH3A2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH3A2 were set to 8528251; 29704247
Phenotypes for gene: ALDH3A2 were set to Sjogren-Larsson syndrome, MIM#270200
Review for gene: ALDH3A2 was set to GREEN
Added comment: Early-onset spastic paraparesis is a feature of the condition. >3 families reported with biallelic variants.
Sources: Expert list
Intellectual disability v3.314 CAMK2G Arina Puzriakova Publications for gene: CAMK2G were set to 26350204; 24896178; 23033978
Intellectual disability v3.313 CAMK2G Arina Puzriakova Phenotypes for gene: CAMK2G were changed from to Mental retardation, autosomal dominant 59, 618522
Intellectual disability v3.312 CAMK2G Arina Puzriakova Mode of pathogenicity for gene: CAMK2G was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.311 CAMK2G Arina Puzriakova Classified gene: CAMK2G as Amber List (moderate evidence)
Intellectual disability v3.311 CAMK2G Arina Puzriakova Added comment: Comment on list classification: Rating has been upgraded from Red to Amber based on the review by Konstantinos Varvagiannis - two unrelated individuals with severe ID, associated with de novo CAMK2G variants, with addition of functional data.
Intellectual disability v3.311 CAMK2G Arina Puzriakova Gene: camk2g has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.310 FIBP Arina Puzriakova Classified gene: FIBP as Amber List (moderate evidence)
Intellectual disability v3.310 FIBP Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber based on review by Zornitza Stark.
Intellectual disability v3.310 FIBP Arina Puzriakova Gene: fibp has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.309 FIBP Arina Puzriakova Phenotypes for gene: FIBP were changed from Thauvin-Robinet-Faivre syndrome to Thauvin-Robinet-Faivre syndrome, 617107
Intellectual disability v3.308 FIBP Arina Puzriakova Added comment: Comment on publications: Two publications (PMID: 26660953; 27183861) describing four individuals from two unrelated families.
Intellectual disability v3.308 FIBP Arina Puzriakova Publications for gene: FIBP were set to 26660953
Intellectual disability v3.307 TANC2 Arina Puzriakova Tag watchlist tag was added to gene: TANC2.
Early onset or syndromic epilepsy v2.152 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Intellectual disability v3.307 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Intellectual disability v3.306 VAMP1 Arina Puzriakova Tag watchlist tag was added to gene: VAMP1.
Intellectual disability v3.306 VAMP1 Arina Puzriakova Phenotypes for gene: VAMP1 were changed from congenital myasthenic syndrome (CMS) and delayed development to Myasthenic syndrome, congenital, 25, 618323
Intellectual disability v3.305 VAMP1 Arina Puzriakova Publications for gene: VAMP1 were set to 28253535
Intellectual disability v3.304 VAMP1 Arina Puzriakova Classified gene: VAMP1 as Green List (high evidence)
Intellectual disability v3.304 VAMP1 Arina Puzriakova Added comment: Comment on list classification: Literature search revealed that developmental delay primarily affects motor function, and it is unclear whether patients exhibit any cognitive deficit. Additional cases would help delineate the association with this phenotype.

Therefore, recommending a rating downgrade from Green to Amber/Red at the next major review, awaiting further publications/clinical evidence.
Intellectual disability v3.304 VAMP1 Arina Puzriakova Gene: vamp1 has been classified as Green List (High Evidence).
Intellectual disability v3.303 VAMP1 Arina Puzriakova Tag for-review tag was added to gene: VAMP1.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Tag for-review tag was added to gene: TRIM32.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Phenotypes for gene: TRIM32 were changed from BARDET-BIEDL SYNDROME TYPE 11 (BBS11) to Bardet-Biedl syndrome 11, 615988
Intellectual disability v3.302 TRIM32 Arina Puzriakova Publications for gene: TRIM32 were set to 0
Intellectual disability v3.301 TRIM32 Arina Puzriakova Classified gene: TRIM32 as Green List (high evidence)
Intellectual disability v3.301 TRIM32 Arina Puzriakova Added comment: Comment on list classification: Recommended Green-to-Red rating downgrade on the next major review - only one family reported to date for association with BBS. Currently also Red on the Bardet-Biedl Syndrome (Version 1.5) gene panel.
Intellectual disability v3.301 TRIM32 Arina Puzriakova Gene: trim32 has been classified as Green List (High Evidence).
Intellectual disability v3.300 VARS2 Arina Puzriakova Classified gene: VARS2 as Amber List (moderate evidence)
Intellectual disability v3.300 VARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - >3 unrelated families with different variants. Severe psychomotor delay was an early and significant manifestation on clinical evaluation.
Intellectual disability v3.300 VARS2 Arina Puzriakova Gene: vars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.299 VARS2 Arina Puzriakova Tag for-review tag was added to gene: VARS2.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Classified gene: SUCLA2 as Amber List (moderate evidence)
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Added comment: Comment on list classification: Although sufficient number of cases with relevant clinical presentation, psychomotor delay is a component of a broader phenotype. Patients are more likely to be recognised via other routes (Metabolic/White Matter Disorders/Mitochondrial) - SUCLA2 is already Green on these PanelApp panels.

Therefore, rating Amber on the ID panel.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Gene: sucla2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.13 LARS2 Sarah Leigh Tag for-review tag was added to gene: LARS2.
Ataxia and cerebellar anomalies - childhood onset v2.13 LARS2 Sarah Leigh edited their review of gene: LARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Leukodystrophy, adult onset v1.6 LARS2 Sarah Leigh Publications for gene: LARS2 were set to 32442335; 30737337
Ataxia and cerebellar anomalies - childhood onset v2.13 LARS2 Sarah Leigh Classified gene: LARS2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.13 LARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Perrault syndrome. At least 6 variants reported as compound heterozygotes in three unrelated cases whose varied phenotypes included ataxia (PMID 30737337).
Ataxia and cerebellar anomalies - childhood onset v2.13 LARS2 Sarah Leigh Gene: lars2 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v1.4 CSNK1D Sarah Leigh reviewed gene: CSNK1D: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paroxysmal central nervous system disorders v1.4 CSNK1D Sarah Leigh Tag for-review tag was added to gene: CSNK1D.
White matter disorders and cerebral calcification - childhood onset v1.14 VPS11 Zornitza Stark reviewed gene: VPS11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27120463, 26307567, 27473128; Phenotypes: Leukodystrophy, hypomyelinating, 12, MIM# 616683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 WARS2 Zornitza Stark gene: WARS2 was added
gene: WARS2 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: WARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS2 were set to 31282308; 28650581; 30920170
Phenotypes for gene: WARS2 were set to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, MIM# 617710
Review for gene: WARS2 was set to GREEN
gene: WARS2 was marked as current diagnostic
Added comment: At least three affected individuals where white matter changes were a prominent feature of the phenotype.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 GNB1 Shekeeb Mohammad reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31034681, 27668284; Phenotypes: Myoclonus, Dystonia, Childhood onset dystonia, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - childhood onset v1.14 ZFYVE26 Zornitza Stark reviewed gene: ZFYVE26: Rating: GREEN; Mode of pathogenicity: None; Publications: 19084844; Phenotypes: Spastic paraplegia 15, autosomal recessive, MIM# 270700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 UFM1 Zornitza Stark gene: UFM1 was added
gene: UFM1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: UFM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFM1 were set to 28931644; 29868776
Phenotypes for gene: UFM1 were set to Leukodystrophy, hypomyelinating, 14, MIM# 617899
Review for gene: UFM1 was set to GREEN
gene: UFM1 was marked as current diagnostic
Added comment: 16 children from Roma descent reported initially, all had homozygous 3bp deletion in the promoter of UFM1 (founder). Another 4 individuals from 2 Sudanese families reported subsequently, with missense variant in gene.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 TUFM Zornitza Stark reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132884, 26741492, 17160893; Phenotypes: Combined oxidative phosphorylation deficiency 4, MIM# 610678, Mitochondrial Leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - childhood onset v1.14 TMEM63A Zornitza Stark gene: TMEM63A was added
gene: TMEM63A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: TMEM63A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63A were set to 31587869
Phenotypes for gene: TMEM63A were set to Leukodystrophy, hypomyelinating, 19, transient infantile, MIM# 618688
Review for gene: TMEM63A was set to GREEN
Added comment: 4 unrelated patients with infantile-onset leukodystrophy with heterozygous variants, three of which were de novo.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 TMEM106B Zornitza Stark edited their review of gene: TMEM106B: Changed mode of pathogenicity: Other
White matter disorders and cerebral calcification - childhood onset v1.14 TMEM106B Zornitza Stark reviewed gene: TMEM106B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29186371, 29444210, 28728022, 30643851; Phenotypes: Leukodystrophy, hypomyelinating, 16 617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - childhood onset v1.14 SPG11 Zornitza Stark reviewed gene: SPG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 18067136; Phenotypes: Spastic paraplegia 11, autosomal recessive, MIM# 604360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 SPART Zornitza Stark reviewed gene: SPART: Rating: GREEN; Mode of pathogenicity: None; Publications: 28875386, 15372254; Phenotypes: Troyer syndrome 275900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 SNORD118 Zornitza Stark reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: None; Publications: 27571260; Phenotypes: Leukoencephalopathy, brain calcifications, and cysts 614561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 SDHA Zornitza Stark reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22972948; Phenotypes: Mitochondrial respiratory chain complex II deficiency, MIM#252011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 RPIA Zornitza Stark gene: RPIA was added
gene: RPIA was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 31247379; 14988808; 31056085
Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM# 608611
Review for gene: RPIA was set to GREEN
Added comment: Four unrelated individuals described to date, variable onset of leukodystrophy in childhood/adolescence, though other symptoms generally precede.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 RAB11B Zornitza Stark reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
White matter disorders and cerebral calcification - childhood onset v1.14 PTEN Zornitza Stark gene: PTEN was added
gene: PTEN was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTEN were set to 29720545; 29152901; 30664625
Phenotypes for gene: PTEN were set to Cowden syndrome 1, MIM# 158350
Review for gene: PTEN was set to GREEN
gene: PTEN was marked as current diagnostic
Added comment: White matter changes described in many individuals.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 POLH Zornitza Stark reviewed gene: POLH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, variant type 278750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 NFU1 Zornitza Stark gene: NFU1 was added
gene: NFU1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: NFU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFU1 were set to 21944046; 22077971; 32747156; 29441221
Phenotypes for gene: NFU1 were set to Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711
Review for gene: NFU1 was set to GREEN
gene: NFU1 was marked as current diagnostic
Added comment: Bi-allelic variants in this gene cause multiple mitochondrial dysfunctions syndrome, a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death. Cavitating leukodystrophy and other white matter changes described in multiple affected individuals.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 NAXE Zornitza Stark reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27122014, 27616477, 31758406; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 NAXD Zornitza Stark gene: NAXD was added
gene: NAXD was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Review for gene: NAXD was set to GREEN
gene: NAXD was marked as current diagnostic
Added comment: Six unrelated families reported.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 MPLKIP Zornitza Stark reviewed gene: MPLKIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy 4, nonphotosensitive 234050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 KIF5A Zornitza Stark gene: KIF5A was added
gene: KIF5A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: KIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5A were set to 27463701; 27414745
Phenotypes for gene: KIF5A were set to Myoclonus, intractable, neonatal, MIM# 617235
Review for gene: KIF5A was set to GREEN
gene: KIF5A was marked as current diagnostic
Added comment: Variants in KIF5A cause a range of phenotypes with variable range of onset including spastic paraplegia and neuropathy. Three unrelated families reported with de novo frame-shifts in the C-terminal domain of KIF5A and neonatal intractable myoclonus, a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants had intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging showed a progressive leukoencephalopathy.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 ISCA2 Zornitza Stark reviewed gene: ISCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25539947, 29297947, 29122497, 29359243; Phenotypes: Multiple mitochondrial dysfunctions syndrome 4, MIM# 616370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 ISCA1 Zornitza Stark gene: ISCA1 was added
gene: ISCA1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122
Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613
Review for gene: ISCA1 was set to GREEN
gene: ISCA1 was marked as current diagnostic
Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families.
Sources: Expert list
Monogenic hearing loss v2.74 COL2A1 Eleanor Williams edited their review of gene: COL2A1: Changed rating: AMBER; Changed publications: 23110709, 27408751, 20179744; Changed phenotypes: Stickler syndrome, type I, 108300; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.74 COL2A1 Eleanor Williams commented on gene: COL2A1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 CTNNBL1 Boaz Palterer edited their review of gene: CTNNBL1: Changed rating: RED
Leukodystrophy, adult onset v1.5 LARS2 Sarah Leigh edited their review of gene: LARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Leukodystrophy, adult onset v1.5 LARS2 Sarah Leigh Tag for-review tag was added to gene: LARS2.
Leukodystrophy, adult onset v1.5 LARS2 Sarah Leigh Classified gene: LARS2 as Amber List (moderate evidence)
Leukodystrophy, adult onset v1.5 LARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Perrault syndrome. At least 10 variants reported as compound heterozygotes in five unrelated cases whose varied phenotypes included leukodystrophy (PMIDs 32442335;30737337).
Leukodystrophy, adult onset v1.5 LARS2 Sarah Leigh Gene: lars2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.7 SVIL Sarah Leigh Tag watchlist tag was added to gene: SVIL.
Congenital myopathy v2.7 SVIL Sarah Leigh Classified gene: SVIL as Amber List (moderate evidence)
Congenital myopathy v2.7 SVIL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two terminating variants reported in two unrelated, consanguineous families with a childhood/adolescence onset myopathy (PMID 32779703).
Congenital myopathy v2.7 SVIL Sarah Leigh Gene: svil has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.6 DHX16 Sarah Leigh Classified gene: DHX16 as Amber List (moderate evidence)
Congenital myopathy v2.6 DHX16 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing. No functional studies were reported.
Congenital myopathy v2.6 DHX16 Sarah Leigh Gene: dhx16 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.14 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18571143, 27405012, 32532876, 28377887, 27405012; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - childhood onset v1.14 HIKESHI Zornitza Stark gene: HIKESHI was added
gene: HIKESHI was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, MIM# 616881
Review for gene: HIKESHI was set to GREEN
gene: HIKESHI was marked as current diagnostic
Added comment: Six children from three unrelated Ashkenazi Jewish families reported, segregating same homozygous variant. Neurodegenerative disorder characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. Other features: visual impairment; cardiac failure during acute illness.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 GTF2H5 Zornitza Stark reviewed gene: GTF2H5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy 3, photosensitive 616395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 GLRX5 Zornitza Stark gene: GLRX5 was added
gene: GLRX5 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: GLRX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLRX5 were set to 24334290; 30770271
Phenotypes for gene: GLRX5 were set to Spasticity, childhood-onset, with hyperglycinemia, MIM# 616859
Review for gene: GLRX5 was set to GREEN
gene: GLRX5 was marked as current diagnostic
Added comment: PMID: 24334290 - 3 patients (3 families) with non-ketotic hyperglycinemia, supported by functional studies. Patients had normal development with childhood-onset spastic paraplegia (3/3), spinal lesion (1/3), optic atrophy (1/3) and brain signal abnormalities involving the frontal and parietal white matter (2/3)

PMID: 30770271 - 1 patient with childhood onset cavitating leukoencephalopathy.

p.Lys51del is a recurring variant.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 GLB1 Zornitza Stark gene: GLB1 was added
gene: GLB1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: GLB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLB1 were set to 25691190
Phenotypes for gene: GLB1 were set to GM1-gangliosidosis, type I, MIM# 230500; GM1-gangliosidosis, type II, MIM# 230600
Review for gene: GLB1 was set to GREEN
gene: GLB1 was marked as current diagnostic
Added comment: Well established gene-disease association, white matter changes are a feature.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 30740813; 29688489
Phenotypes for gene: FIG4 were set to Charcot-Marie-Tooth disease, type 4J 611228; Yunis-Varon syndrome 216340; leukoencephalopathy
Review for gene: FIG4 was set to GREEN
gene: FIG4 was marked as current diagnostic
Added comment: Four unrelated families reported with bi-allelic variants in this gene and a leukoencephalopathy phenotype. Mouse model recapitulates the phenotype. Please note gene is associated with multiple other phenotypes including Yunis-Varon syndrome, CMT, ALS
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 FA2H Zornitza Stark reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: None; Publications: 31837835, 30446360, 22965561, 21592092; Phenotypes: Spastic paraplegia 35, autosomal recessive, MIM# 612319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebrooculofacioskeletal syndrome 3 616570, Xeroderma pigmentosum, group G 278780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 ERCC4 Zornitza Stark reviewed gene: ERCC4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, group F, MIM# 278760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 ERCC3 Zornitza Stark reviewed gene: ERCC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy 2, photosensitive 616390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 ERCC2 Zornitza Stark reviewed gene: ERCC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29451896; Phenotypes: Trichothiodystrophy 1, photosensitive 601675; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 ERCC1 Zornitza Stark reviewed gene: ERCC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebrooculofacioskeletal syndrome 4 610758; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 EPRS Zornitza Stark gene: EPRS was added
gene: EPRS was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 29576217
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15, MIM# 617951
Review for gene: EPRS was set to GREEN
gene: EPRS was marked as current diagnostic
Added comment: Four unrelated families reported with this neurodegenerative disorder. Onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, dysphagia, severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 DEGS1 Zornitza Stark gene: DEGS1 was added
gene: DEGS1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DEGS1 were set to 30620338; 30620337
Phenotypes for gene: DEGS1 were set to Leukodystrophy, hypomyelinating, 18, MIM#618404
Review for gene: DEGS1 was set to GREEN
gene: DEGS1 was marked as current diagnostic
Added comment: 20 individuals from 14 unrelated families. Hypomyelinating leukodystorphy is the prominent feature of this condition.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 DCAF17 Zornitza Stark gene: DCAF17 was added
gene: DCAF17 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: DCAF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF17 were set to 19026396; 20507343
Phenotypes for gene: DCAF17 were set to Woodhouse-Sakati syndrome, MIM# 241080
Review for gene: DCAF17 was set to GREEN
gene: DCAF17 was marked as current diagnostic
Added comment: White matter changes are part of the phenotype.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 CYP7B1 Zornitza Stark reviewed gene: CYP7B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24117163, 19439420, 19187859; Phenotypes: Spastic paraplegia 5A, autosomal recessive, MIM# 270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - childhood onset v1.14 COA7 Zornitza Stark gene: COA7 was added
gene: COA7 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: COA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COA7 were set to 27683825; 29718187
Phenotypes for gene: COA7 were set to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MIM#618387
Review for gene: COA7 was set to GREEN
gene: COA7 was marked as current diagnostic
Added comment: At least 3 unrelated cases reported with leukoencephalopathy as a feature of the condition. Paediatric age of onset.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 CNTNAP1 Zornitza Stark reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29882456; Phenotypes: Hypomyelinating neuropathy, congenital, 3, MIM# 618186, Lethal congenital contracture syndrome 7, MIM# 616286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.14 CLPP Zornitza Stark gene: CLPP was added
gene: CLPP was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 27899912
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to GREEN
gene: CLPP was marked as current diagnostic
Added comment: Prominent white matter changes identified in at least three unrelated individuals.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 BOLA3 Zornitza Stark reviewed gene: BOLA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30302924, 29654549, 30302924; Phenotypes: Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, MIM# 614299; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - childhood onset v1.14 APOPT1 Zornitza Stark gene: APOPT1 was added
gene: APOPT1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOPT1 were set to 25175347
Phenotypes for gene: APOPT1 were set to Mitochondrial complex IV deficiency, MIM# 220110
Review for gene: APOPT1 was set to GREEN
gene: APOPT1 was marked as current diagnostic
Added comment: Cavitating leukodystrophy reported as part of this mitochondrial disorder, onset described as late infancy/early childhood.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 AP4B1 Zornitza Stark gene: AP4B1 was added
gene: AP4B1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 29193663
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive MIM#614066
Review for gene: AP4B1 was set to GREEN
gene: AP4B1 was marked as current diagnostic
Added comment: White matter changes have been reported as a feature of the condition in at least ten unrelated cases with biallelic variants. The onset of the condition is in childhood.
Sources: Expert list
Intellectual disability v3.298 FRY Arina Puzriakova Publications for gene: FRY were set to 21937992
Intellectual disability v3.297 FRY Arina Puzriakova Classified gene: FRY as Amber List (moderate evidence)
Intellectual disability v3.297 FRY Arina Puzriakova Gene: fry has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.296 ELN Arina Puzriakova Classified gene: ELN as Red List (low evidence)
Intellectual disability v3.296 ELN Arina Puzriakova Gene: eln has been classified as Red List (Low Evidence).
Intellectual disability v3.295 ELN Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis.
White matter disorders and cerebral calcification - childhood onset v1.14 AIFM1 Zornitza Stark gene: AIFM1 was added
gene: AIFM1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AIFM1 were set to 28842795; 27102849
Phenotypes for gene: AIFM1 were set to Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, MIM# 300232
Review for gene: AIFM1 was set to GREEN
Added comment: Seven unrelated families reported with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL), an X-linked recessive developmental disorder characterised by slowly progressive skeletal and neurologic abnormalities, including short stature, large and deformed joints, significant motor impairment, visual defects, and sometimes cognitive deficits. Affected individuals typically have normal early development in the first year or so of life, followed by development regression and the development of symptoms. Brain imaging shows white matter abnormalities consistent with hypomyelinating leukodystrophy.
Sources: Expert list
White matter disorders and cerebral calcification - childhood onset v1.14 AARS Zornitza Stark gene: AARS was added
gene: AARS was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 28493438; 25817015
Phenotypes for gene: AARS were set to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Review for gene: AARS was set to GREEN
gene: AARS was marked as current diagnostic
Added comment: Bi-allelic variants associated with a severe phenotype comprising leukodystrophy, epilepsy, microcephaly and neurodevelopmental delay reported in three families.
Sources: Expert list
Haematological malignancies cancer susceptibility v2.3 TSR2 Zornitza Stark reviewed gene: TSR2: Rating: RED; Mode of pathogenicity: None; Publications: 24942156; Phenotypes: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, MIM# 300946; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cytopenia - NOT Fanconi anaemia v1.6 SRP54 Zornitza Stark gene: SRP54 was added
gene: SRP54 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert list
Mode of inheritance for gene: SRP54 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRP54 were set to 28972538
Phenotypes for gene: SRP54 were set to Syndromic neutropenia with Shwachman-Diamond-like features
Review for gene: SRP54 was set to GREEN
gene: SRP54 was marked as current diagnostic
Added comment: 3 unrelated families presented with neutropaenia associated with other symptoms, including exocrine pancreatic deficiency and/or autistic behavior, phenotypic overlap with Swachman-Diamond syndrome.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark changed review comment from: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. PMID 23718193, cannot find RPL9 variant in main results table.; to: PMID: 29114930, de novo splice site variant, c.-2+1G>C, functional impact of this variant is likely deleterious but not proven. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. PMID 23718193, cannot find RPL9 variant in main results table.
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark edited their review of gene: RPL9: Changed rating: RED
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark changed review comment from: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. ; to: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. PMID 23718193, cannot find RPL9 variant in main results table.
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark changed review comment from: PMID: 29114930, de novo splice site variant, c.-2+1G>C.; to: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad.
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark reviewed gene: RPL9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond Blackfan anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.6 RPL31 Zornitza Stark reviewed gene: RPL31: Rating: AMBER; Mode of pathogenicity: None; Publications: 25042156, 25424902; Phenotypes: Diamond Blackfan anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.6 RPL26 Zornitza Stark reviewed gene: RPL26: Rating: RED; Mode of pathogenicity: None; Publications: 22431104; Phenotypes: Diamond-Blackfan anemia 11, MIM# 614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.6 NPM1 Zornitza Stark gene: NPM1 was added
gene: NPM1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert list
Mode of inheritance for gene: NPM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPM1 were set to 31570891
Phenotypes for gene: NPM1 were set to radial ray defects; short stature; nail dsytrophy; bone marrow failure
Review for gene: NPM1 was set to GREEN
gene: NPM1 was marked as current diagnostic
Added comment: Two unrelated individuals with a dyskeratosis congenita phenotype and extensive functional data to support gene-disease relationship.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.6 NOP10 Zornitza Stark reviewed gene: NOP10: Rating: RED; Mode of pathogenicity: None; Publications: 17507419; Phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.6 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 MYSM1 Zornitza Stark reviewed gene: MYSM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24288411, 28115216, 26220525, 32640305; Phenotypes: Bone marrow failure syndrome 4, MIM#618116; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 KIF23 Zornitza Stark reviewed gene: KIF23: Rating: RED; Mode of pathogenicity: None; Publications: 23570799; Phenotypes: Congenital dyserythropoietic anemia type III; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.6 HOXA11 Zornitza Stark reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia, adult onset v2.9 ERCC4 Zornitza Stark gene: ERCC4 was added
gene: ERCC4 was added to Hereditary ataxia - adult onset. Sources: Expert list
Mode of inheritance for gene: ERCC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC4 were set to 29403087; 28431612; 29892709
Phenotypes for gene: ERCC4 were set to Cerebellar ataxia; Xeroderma pigmentosum, group F, MIM# 278760
Review for gene: ERCC4 was set to GREEN
gene: ERCC4 was marked as current diagnostic
Added comment: Bi-allelic variants in ERCC4 cause a range of phenotypes, including xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anaemia. Seven unrelated individuals reported with slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with onset in adolescence/adulthood. Brain MRIs demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild in 5/7: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.6 DDX41 Zornitza Stark reviewed gene: DDX41: Rating: GREEN; Mode of pathogenicity: None; Publications: 31698430, 31484648; Phenotypes: {Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to} MIM# 616871; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 AK2 Zornitza Stark gene: AK2 was added
gene: AK2 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert list
Mode of inheritance for gene: AK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AK2 were set to 19043416
Phenotypes for gene: AK2 were set to Reticular dysgenesis, MIM# 267500
Review for gene: AK2 was set to GREEN
gene: AK2 was marked as current diagnostic
Added comment: Well established gene-disease association.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 AP1S2 Zornitza Stark reviewed gene: AP1S2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, X-linked syndromic 5, Pettigrew syndrome, 304340; Mode of inheritance: None
Hereditary ataxia, adult onset v2.9 AMPD2 Zornitza Stark reviewed gene: AMPD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hyoplasia 9, 615809; Mode of inheritance: None
Hereditary ataxia, adult onset v2.9 ADGRG1 Zornitza Stark reviewed gene: ADGRG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.9 ABCB7 Zornitza Stark reviewed gene: ABCB7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anemia, sideroblastic, with ataxia 301310; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - childhood onset v2.12 XRCC1 Zornitza Stark reviewed gene: XRCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28002403, 29472272; Phenotypes: Spinocerebellar ataxia, autosomal recessive 26 MIM#617633; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia, adult onset v2.9 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: RED; Mode of pathogenicity: None; Publications: 28007905, 23359680, 11555633; Phenotypes: Spastic paraplegia 79, autosomal recessive, MIM#615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28007905, 23359680, 11555633; Phenotypes: Spastic paraplegia 79, autosomal recessive, MIM#615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ataxia and cerebellar anomalies - childhood onset v2.12 UBTF Zornitza Stark gene: UBTF was added
gene: UBTF was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: UBTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBTF were set to 29300972
Phenotypes for gene: UBTF were set to Neurodegeneration, childhood-onset, with brain atrophy MIM#617672
Review for gene: UBTF was set to GREEN
gene: UBTF was marked as current diagnostic
Added comment: Paediatric ataxia reported as a feature of the condition in 4 unrelated cases with de novo missense variants.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 TMEM106B Zornitza Stark gene: TMEM106B was added
gene: TMEM106B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM106B were set to 29186371; 29444210
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16, MIM# 617964
Review for gene: TMEM106B was set to GREEN
gene: TMEM106B was marked as current diagnostic
Added comment: Cerebellar signs including ataxia prominent.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 TGM6 Zornitza Stark reviewed gene: TGM6: Rating: RED; Mode of pathogenicity: None; Publications: 32426513, 30670339; Phenotypes: Spinocerebellar ataxia 35, MIM# 613908; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v2.12 TDP2 Zornitza Stark gene: TDP2 was added
gene: TDP2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: TDP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: At least 6 individuals from 4 unrelated families reported.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 TBC1D23 Zornitza Stark reviewed gene: TBC1D23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia, type 11, MIM# 617695; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 TBC1D23 Zornitza Stark gene: TBC1D23 was added
gene: TBC1D23 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: TBC1D23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D23 were set to 28823707; 28823706
Phenotypes for gene: TBC1D23 were set to Pontocerebellar hypoplasia, type 11, MIM# 617695
Review for gene: TBC1D23 was set to GREEN
gene: TBC1D23 was marked as current diagnostic
Added comment: Seven unrelated families reported, ataxia is part of the phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SVBP Zornitza Stark gene: SVBP was added
gene: SVBP was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SVBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVBP were set to 31363758; 30607023
Phenotypes for gene: SVBP were set to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569
Review for gene: SVBP was set to GREEN
gene: SVBP was marked as current diagnostic
Added comment: 5 families with homozygous mutations in SVBP; syndromic cause of paediatric ataxia. Some shared same founder variant, p.Q28*. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SQSTM1 Zornitza Stark gene: SQSTM1 was added
gene: SQSTM1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SQSTM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQSTM1 were set to 27545679
Phenotypes for gene: SQSTM1 were set to Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145
Review for gene: SQSTM1 was set to GREEN
gene: SQSTM1 was marked as current diagnostic
Added comment: Four unrelated families, presenting feature of this progressive neurological disorder was ataxia.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SPR Zornitza Stark gene: SPR was added
gene: SPR was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SPR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SPR were set to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716
Review for gene: SPR was set to GREEN
gene: SPR was marked as current diagnostic
Added comment: Complex movement disorder, dystonia predominant, but ataxia described in some individuals. Most individuals have had bi-allelic variants identified, uncertain whether there is an association with mono-allelic variants.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SPG7 Zornitza Stark reviewed gene: SPG7: Rating: AMBER; Mode of pathogenicity: None; Publications: 32893728; Phenotypes: Spastic paraplegia 7, autosomal recessive, MIM# 607259; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 SNAP25 Zornitza Stark gene: SNAP25 was added
gene: SNAP25 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNAP25 were set to 29491473; 25381298; 17283335
Phenotypes for gene: SNAP25 were set to Myasthenic syndrome, congenital, 18, 616330; cerebellar ataxia and seizures
Review for gene: SNAP25 was set to GREEN
gene: SNAP25 was marked as current diagnostic
Added comment: Phenotype in 3 reported cases and mouse model includes ataxia as a feature.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 SLC9A1 Zornitza Stark reviewed gene: SLC9A1: Rating: RED; Mode of pathogenicity: None; Publications: 25205112, 30018422, 25760855; Phenotypes: Lichtenstein-Knorr syndrome, MIM# 616291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 SLC9A1 Zornitza Stark gene: SLC9A1 was added
gene: SLC9A1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC9A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC9A1 were set to 25205112; 30018422; 25760855
Phenotypes for gene: SLC9A1 were set to Lichtenstein-Knorr syndrome, MIM# 616291
Review for gene: SLC9A1 was set to AMBER
Added comment: Two families with bi-allelic variants in this gene reported and combination of deafness and ataxia.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SLC52A2 Zornitza Stark gene: SLC52A2 was added
gene: SLC52A2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC52A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC52A2 were set to 30377535
Phenotypes for gene: SLC52A2 were set to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707
Review for gene: SLC52A2 was set to GREEN
gene: SLC52A2 was marked as current diagnostic
Added comment: Generally presents with a range of neuropathies but ataxia described. Treatable condition.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SLC25A46 Zornitza Stark gene: SLC25A46 was added
gene: SLC25A46 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC25A46 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A46 were set to 30178502; 26168012; 27543974; 27430653; 27390132; 28934388; 28558379
Phenotypes for gene: SLC25A46 were set to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Review for gene: SLC25A46 was set to GREEN
gene: SLC25A46 was marked as current diagnostic
Added comment: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus.

At least 10 unrelated families reported, supportive functional data.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SLC17A5 Zornitza Stark gene: SLC17A5 was added
gene: SLC17A5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC17A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC17A5 were set to 26171070
Phenotypes for gene: SLC17A5 were set to Sialic acid storage disorder, infantile, MIM# 269920
Review for gene: SLC17A5 was set to GREEN
gene: SLC17A5 was marked as current diagnostic
Added comment: Ataxia is prominent in childhood.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 SCYL1 Zornitza Stark reviewed gene: SCYL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 SCYL1 Zornitza Stark gene: SCYL1 was added
gene: SCYL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SCYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL1 were set to 29419818; 17571074; 26581903; 30531813
Phenotypes for gene: SCYL1 were set to Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719
Review for gene: SCYL1 was set to GREEN
gene: SCYL1 was marked as current diagnostic
Added comment: Early-onset ataxia (<1 year) with recurrent episodes of liver failure, sensory-motor axonal neuropathy, cerebellar atrophy. At least 7 unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31904124, 31887642, 31675620; Phenotypes: Cognitive impairment with or without cerebellar ataxia, MIM# 614306, Epileptic encephalopathy, early infantile, 13, MIM# 614558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Ataxia and cerebellar anomalies - childhood onset v2.12 SCN2A Zornitza Stark gene: SCN2A was added
gene: SCN2A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SCN2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN2A were set to 31924505; 32893078; 31904126
Phenotypes for gene: SCN2A were set to Epileptic encephalopathy, early infantile, 11, MIM# 613721
Review for gene: SCN2A was set to GREEN
gene: SCN2A was marked as current diagnostic
Added comment: Classically presents with seizures and DD/ID although a range of other manifestations reported, including movement abnormalities, including ataxia, especially episodic ataxia.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SCN1A Zornitza Stark gene: SCN1A was added
gene: SCN1A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SCN1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN1A were set to 27264139; 27817982; 28732259
Phenotypes for gene: SCN1A were set to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208
Review for gene: SCN1A was set to GREEN
gene: SCN1A was marked as current diagnostic
Added comment: Ataxia is part of the phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 SAR1B Zornitza Stark reviewed gene: SAR1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chylomicron retention disease, 246700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 RUBCN Zornitza Stark reviewed gene: RUBCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20826435, 30237576, 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, MIM#615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia, adult onset v2.9 RORA Zornitza Stark reviewed gene: RORA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v2.12 RORA Zornitza Stark gene: RORA was added
gene: RORA was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: RORA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RORA were set to 29656859
Phenotypes for gene: RORA were set to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060
Review for gene: RORA was set to GREEN
gene: RORA was marked as current diagnostic
Added comment: 11 unrelated individuals with syndromic intellectual disability and de novo variants in this gene. Severity varied from mild borderline intellectual disability with mild speech delay or normal speech, through to severe cognitive impairment with poor or absent speech. Most had ataxia, hypotonia, poor coordination, and/or mild tremor, suggesting cerebellar dysfunction. Three individuals had documented cerebellar hypoplasia or pontocerebellar atrophy on brain imaging. Seven had seizures of variable types, including neonatal myoclonic, tonic-clonic, multifocal, generalized, and absence. Five were diagnosed with autism spectrum disorder. More variable features included strabismus, esotropia, nystagmus, and oculomotor apraxia. Postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 PRICKLE1 Zornitza Stark reviewed gene: PRICKLE1: Rating: RED; Mode of pathogenicity: None; Publications: 20301774; Phenotypes: Epilepsy, progressive myoclonic 1B, MIM# 612437; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.12 POLR3B Zornitza Stark gene: POLR3B was added
gene: POLR3B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: POLR3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3B were set to 22036171; 22036172
Phenotypes for gene: POLR3B were set to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 614381
Review for gene: POLR3B was set to GREEN
gene: POLR3B was marked as current diagnostic
Added comment: Ataxia is a presenting feature.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 PMPCB Zornitza Stark gene: PMPCB was added
gene: PMPCB was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCB were set to 29576218
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954
Review for gene: PMPCB was set to GREEN
gene: PMPCB was marked as current diagnostic
Added comment: Progressive disorder, includes ataxia. Four unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 PITRM1 Zornitza Stark gene: PITRM1 was added
gene: PITRM1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: PITRM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PITRM1 were set to 26697887; 29764912; 29383861
Phenotypes for gene: PITRM1 were set to Ataxia; Intellectual disability
Review for gene: PITRM1 was set to GREEN
gene: PITRM1 was marked as current diagnostic
Added comment: Three families with two unique variants and in vitro functional assays. Cases and mouse model have spinocerebellar ataxia as a prominent feature of the phenotype. No OMIM phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 OPA1 Zornitza Stark edited their review of gene: OPA1: Set current diagnostic: yes
Ataxia and cerebellar anomalies - childhood onset v2.12 OPA1 Zornitza Stark gene: OPA1 was added
gene: OPA1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: OPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OPA1 were set to 28494813
Phenotypes for gene: OPA1 were set to Optic atrophy plus syndrome, MIM# 125250
Review for gene: OPA1 was set to GREEN
Added comment: Syndromic optic atrophy, also known as DOA+ syndrome, is a neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia (PEO), muscle cramps, hyperreflexia, and ataxia. See PMID 28494813 for three unrelated children where ataxia was a prominent part of the phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 NKX2-1 Zornitza Stark gene: NKX2-1 was added
gene: NKX2-1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: NKX2-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NKX2-1 were set to 10931427; 27066577; 26839702; 26103969
Phenotypes for gene: NKX2-1 were set to Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700
Review for gene: NKX2-1 was set to GREEN
gene: NKX2-1 was marked as current diagnostic
Added comment: Paediatric onset ataxia reported in greater than 3 families with the condition.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 MVK Zornitza Stark reviewed gene: MVK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12563048, 10401001, 28095071; Phenotypes: Mevalonic aciduria MIM#610377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 MTFMT Zornitza Stark gene: MTFMT was added
gene: MTFMT was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: MTFMT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTFMT were set to 26060307; 24461907
Phenotypes for gene: MTFMT were set to Combined oxidative phosphorylation deficiency 15 MIM#614947; Mitochondrial complex I deficiency, nuclear type 27 MIM#618248
Review for gene: MTFMT was set to GREEN
gene: MTFMT was marked as current diagnostic
Added comment: Five unrelated cases reported with paediatric onset ataxia as a prominent feature of the condition.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 MSTO1 Zornitza Stark gene: MSTO1 was added
gene: MSTO1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: MSTO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MSTO1 were set to 28554942; 28544275; 31604776; 31463572; 31130378; 30684668; 29339779
Phenotypes for gene: MSTO1 were set to Myopathy, mitochondrial, and ataxia, MIM# 617675
Review for gene: MSTO1 was set to GREEN
gene: MSTO1 was marked as current diagnostic
Added comment: Impaired mitochondrial fusion disorder. Multiple families reported with bi-allelic variants and childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy and ataxia. One family reported with heterozygous variant in this gene, gene-disease association for mono allelic variants not well established.
Sources: Expert list
Leukodystrophy, adult onset v1.4 LARS2 Zornitza Stark gene: LARS2 was added
gene: LARS2 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: LARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS2 were set to 32442335; 30737337
Phenotypes for gene: LARS2 were set to Leukodystrophy
Review for gene: LARS2 was set to GREEN
gene: LARS2 was marked as current diagnostic
Added comment: Five individuals reported where leukodystrophy was part of LARS2-associated Perrault syndrome. Neurological decline and MRI abnormalities were primarily in adulthood.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 LARS2 Zornitza Stark gene: LARS2 was added
gene: LARS2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: LARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS2 were set to 29205794; 32423379; 30737337
Phenotypes for gene: LARS2 were set to Perrault syndrome 4, MIM# 615300; Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Leukodystrophy
Review for gene: LARS2 was set to GREEN
gene: LARS2 was marked as current diagnostic
Added comment: Bi-allelic variants in LARS2 cause a range of phenotypes, with some individuals displaying neurological features, including at least three individuals reported with ataxia (reviewed in PMID 32423379)
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 LAMA1 Zornitza Stark gene: LAMA1 was added
gene: LAMA1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA1 were set to 25105227
Phenotypes for gene: LAMA1 were set to Cerebellar ataxia, intellectual disability, oculomotor apraxia, cerebellar cysts; Poretti Boltshauser syndrome MIM#615960
Review for gene: LAMA1 was set to GREEN
gene: LAMA1 was marked as current diagnostic
Added comment: Five unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 KCNA2 Zornitza Stark gene: KCNA2 was added
gene: KCNA2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: KCNA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA2 were set to 29050392
Phenotypes for gene: KCNA2 were set to Early infantile encephalopathy 32, MIM#616366
Review for gene: KCNA2 was set to GREEN
gene: KCNA2 was marked as current diagnostic
Added comment: Ataxia is part of the phenotype.

Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 IRF2BPL Zornitza Stark gene: IRF2BPL was added
gene: IRF2BPL was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: IRF2BPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF2BPL were set to 30057031
Phenotypes for gene: IRF2BPL were set to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088
Review for gene: IRF2BPL was set to GREEN
gene: IRF2BPL was marked as current diagnostic
Added comment: Progressive ataxia is a feature reported in the original cohort of 7 unrelated patients.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 FBXL4 Zornitza Stark gene: FBXL4 was added
gene: FBXL4 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: FBXL4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL4 were set to 28383868
Phenotypes for gene: FBXL4 were set to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), MIM# 615471
Review for gene: FBXL4 was set to GREEN
Added comment: Ataxia is a reported feature of this mitochondrial disorder.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 FA2H Zornitza Stark gene: FA2H was added
gene: FA2H was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FA2H were set to 31135052
Phenotypes for gene: FA2H were set to Spastic paraplegia 35, autosomal recessive MIM#612319
Review for gene: FA2H was set to GREEN
Added comment: Limb ataxia is reported as a feature of the condition in at least 13 cases with mainly paediatric onset.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 EBF3 Zornitza Stark reviewed gene: EBF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypotonia, ataxia, and delayed development syndrome, MIM# 617330; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v2.12 EBF3 Zornitza Stark gene: EBF3 was added
gene: EBF3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: EBF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EBF3 were set to 28017373; 28017372; 28017370; 32366537
Phenotypes for gene: EBF3 were set to Hypotonia, ataxia, and delayed development syndrome, MIM# 617330
Review for gene: EBF3 was set to GREEN
gene: EBF3 was marked as current diagnostic
Added comment: Twenty unrelated families reported with mono-allelic variants in this gene and HADDS, a neurodevelopmental syndrome characterised by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 DOCK3 Zornitza Stark gene: DOCK3 was added
gene: DOCK3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: DOCK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOCK3 were set to 28195318; 29130632; 30976111
Phenotypes for gene: DOCK3 were set to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, MIM#618292
Review for gene: DOCK3 was set to GREEN
gene: DOCK3 was marked as current diagnostic
Added comment: Five unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: RED; Mode of pathogenicity: None; Publications: 10921354; Phenotypes: Dyskeratosis congenita, X-linked, MIM# 305000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - childhood onset v2.12 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM#615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 CSTB Zornitza Stark reviewed gene: CSTB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), MIM# 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 COA7 Zornitza Stark gene: COA7 was added
gene: COA7 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: COA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COA7 were set to 29718187; 27683825
Phenotypes for gene: COA7 were set to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3, MIM#618387
Review for gene: COA7 was set to GREEN
gene: COA7 was marked as current diagnostic
Added comment: Five unrelated individuals reported with bi-allelic variants in this gene. Slowly progressive condition with variable onset, but at least three individuals presented at <5 years of age.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 CLPP Zornitza Stark gene: CLPP was added
gene: CLPP was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 25254289
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to GREEN
gene: CLPP was marked as current diagnostic
Added comment: Neurological abnormalities including cerebellar ataxia are present in some individuals with this condition.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 CLN5 Zornitza Stark edited their review of gene: CLN5: Set current diagnostic: yes
Ataxia and cerebellar anomalies - childhood onset v2.12 CLN5 Zornitza Stark gene: CLN5 was added
gene: CLN5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: CLN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN5 were set to 25359263
Phenotypes for gene: CLN5 were set to Ceroid lipofuscinosis, neuronal, 5, MIM# 256731
Review for gene: CLN5 was set to GREEN
Added comment: Ataxia is part of the phenotype of this disorder, which is typically of paediatric onset. Please also note report of adult-onset ataxia in PMID 25359263.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 BBS1 Zornitza Stark gene: BBS1 was added
gene: BBS1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: BBS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBS1 were set to 15637713
Phenotypes for gene: BBS1 were set to Bardet-Biedl syndrome 1, MIM#209900
Review for gene: BBS1 was set to GREEN
gene: BBS1 was marked as current diagnostic
Added comment: Ataxia is a common feature of the phenotype.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 ATP8A2 Zornitza Stark reviewed gene: ATP8A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar ataxia, mental retardation and dysequilibirum syndrome 4; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.12 ATP8A2 Zornitza Stark reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22892528, 31612321; Phenotypes: Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4, MIM#615268; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 ATCAY Zornitza Stark reviewed gene: ATCAY: Rating: AMBER; Mode of pathogenicity: None; Publications: 14556008; Phenotypes: Ataxia, cerebellar, Cayman type, MIM# 601238; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.12 ALDH5A1 Zornitza Stark gene: ALDH5A1 was added
gene: ALDH5A1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: ALDH5A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH5A1 were set to 14635103
Phenotypes for gene: ALDH5A1 were set to Succinic semialdehyde dehydrogenase deficiency, MIM# 271980
Review for gene: ALDH5A1 was set to GREEN
gene: ALDH5A1 was marked as current diagnostic
Added comment: Over 50 unrelated families reported. Ataxia is part of the phenotype, which also includes developmental delay, hypotonia, intellectual disability, seizures, hyperkinetic behaviour, aggression, and sleep disturbances.
Sources: Expert list
Hereditary ataxia, adult onset v2.9 ADPRHL2 Zornitza Stark reviewed gene: ADPRHL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.12 ADPRHL2 Zornitza Stark gene: ADPRHL2 was added
gene: ADPRHL2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: ADPRHL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADPRHL2 were set to 30100084; 30401461
Phenotypes for gene: ADPRHL2 were set to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170
Review for gene: ADPRHL2 was set to GREEN
gene: ADPRHL2 was marked as current diagnostic
Added comment: Fourteen unrelated families reported with stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS), an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. The disorder is characterised by cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some individuals develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy.
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v2.12 ACO2 Zornitza Stark gene: ACO2 was added
gene: ACO2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: ACO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACO2 were set to 32519519
Phenotypes for gene: ACO2 were set to Infantile cerebellar-retinal degeneration, MIM#614559
Review for gene: ACO2 was set to GREEN
gene: ACO2 was marked as current diagnostic
Added comment: Ataxia is part of the phenotype, particularly in more mildly affected individuals, where it can be the presenting feature.
Sources: Expert list
Monogenic hearing loss v2.74 COL11A1 Eleanor Williams Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II, 604841Marshall syndrome, 154780{Lumbar disc herniation, susceptibility to}, 603932Fibrochondrogenesis, 228520; Sticklersyndrome,typeII,604841 to Stickler syndrome, type II, MIM#604841; Deafness, autosomal dominant 37, MIM#618533
Monogenic hearing loss v2.73 COL11A1 Eleanor Williams Publications for gene: COL11A1 were set to
Monogenic hearing loss v2.72 COL11A1 Eleanor Williams Mode of inheritance for gene: COL11A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.71 COL11A1 Eleanor Williams Classified gene: COL11A1 as Amber List (moderate evidence)
Monogenic hearing loss v2.71 COL11A1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 1 case of non-syndromic hearing loss in a large pedigree. Other reports are from patients with Stickler/Marshal syndrome.
Monogenic hearing loss v2.71 COL11A1 Eleanor Williams Gene: col11a1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.70 COL11A1 Eleanor Williams reviewed gene: COL11A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30245514, 17236192; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.70 ATP6V1B2 Eleanor Williams Phenotypes for gene: ATP6V1B2 were changed from to Deafness, congenital, with onychodystrophy, autosomal dominant, 124480; Zimmermann-Laband syndrome 2, 616455
Monogenic hearing loss v2.69 ATP6V1B2 Eleanor Williams Publications for gene: ATP6V1B2 were set to
Monogenic hearing loss v2.68 ATP6V1B2 Eleanor Williams Tag for-review tag was added to gene: ATP6V1B2.
Monogenic hearing loss v2.68 ATP6V1B2 Eleanor Williams changed review comment from: Comment on list classification: The rating of this gene should be reviewed after consultation with the Genomics England clinical team and at the next GMS review.; to: Comment on list classification: Sufficient cases with Deafness, congenital, with onychodystrophy to rate green. This gene should be reviewed at the next GMS update.
Monogenic hearing loss v2.68 ATP6V1B2 Eleanor Williams changed review comment from: Adding gene at request of Alistair Pagnamenta (University of Oxford).

PMID: 32873933 Beauregard-Lacroix et al 2020 - identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. All individuals presented with deafness as well as as onychodystrophy and abnormal fingers and/or toes. In addition, all families but one had developmental delay or intellectual disability and five individuals had epilepsy. Two additional familes with dominant deafness onychodystrophy (DDOD) syndrome also had the same variant in ATP6V1B2. Abstract only accessed.
Sources: Expert Review, Literature; to: Adding gene at request of Alistair Pagnamenta (University of Oxford).

Associated with Deafness, congenital, with onychodystrophy, autosomal dominant #124480 (AD) and Zimmermann-Laband syndrome 2 #616455 (AD) in OMIM.

PMID: 32873933 Beauregard-Lacroix et al 2020 - identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. All individuals presented with deafness as well as as onychodystrophy and abnormal fingers and/or toes. In addition, all families but one had developmental delay or intellectual disability and five individuals had epilepsy. Two additional familes with dominant deafness onychodystrophy (DDOD) syndrome also had the same variant in ATP6V1B2. Abstract only accessed.

PMID: 28396750 Menendez et al 2017 - report a Guatemalan famliy with one child with deafness–onychodystrophy. The proband was found to be heterozygous for c.1516C>T [p.(Arg506*)] in ATP6V1B2. Neither parents or sisters had this variant.

PMID: 24913193 Yuan et al 2014 - report 3 Chinese families with severe congenital sensorineural hearing loss, absence of nails and aplasia of the middle phalanx in the fifth fingers, but no inner ear malformation or intellectual disability. Using exome sequencing an identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands. In the third family the same variant was found by Sanger sequencing. A cochlea-specific Atp6v1b2-knockdown mouse model demonstrates that Atp6v1b2 deficiency leads to severe sensorineural hearing loss.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 FNIP1 Boaz Palterer gene: FNIP1 was added
gene: FNIP1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FNIP1 were set to 32905580
Phenotypes for gene: FNIP1 were set to Primary Immunodeficiency; Agammaglobulinemia; Hypertrophic Cardiomyopathy; Neutropenia
Penetrance for gene: FNIP1 were set to unknown
Review for gene: FNIP1 was set to AMBER
Added comment: Sources: Literature
Monogenic hearing loss v2.68 ATP6V1B2 Eleanor Williams Classified gene: ATP6V1B2 as Amber List (moderate evidence)
Monogenic hearing loss v2.68 ATP6V1B2 Eleanor Williams Gene: atp6v1b2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.67 ATP6V1B2 Eleanor Williams Classified gene: ATP6V1B2 as Red List (low evidence)
Monogenic hearing loss v2.67 ATP6V1B2 Eleanor Williams Added comment: Comment on list classification: The rating of this gene should be reviewed after consultation with the Genomics England clinical team and at the next GMS review.
Monogenic hearing loss v2.67 ATP6V1B2 Eleanor Williams Gene: atp6v1b2 has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.66 ATP6V1B2 Eleanor Williams edited their review of gene: ATP6V1B2: Changed rating: GREEN
Monogenic hearing loss v2.66 ATP6V1B2 Eleanor Williams gene: ATP6V1B2 was added
gene: ATP6V1B2 was added to Hearing loss. Sources: Expert Review,Literature
Mode of inheritance for gene: ATP6V1B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added comment: Adding gene at request of Alistair Pagnamenta (University of Oxford).

PMID: 32873933 Beauregard-Lacroix et al 2020 - identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. All individuals presented with deafness as well as as onychodystrophy and abnormal fingers and/or toes. In addition, all families but one had developmental delay or intellectual disability and five individuals had epilepsy. Two additional familes with dominant deafness onychodystrophy (DDOD) syndrome also had the same variant in ATP6V1B2. Abstract only accessed.
Sources: Expert Review, Literature
Monogenic hearing loss v2.65 SOX2 Eleanor Williams Tag for-review tag was added to gene: SOX2.
Monogenic hearing loss v2.65 SOX2 Eleanor Williams Classified gene: SOX2 as Green List (high evidence)
Monogenic hearing loss v2.65 SOX2 Eleanor Williams Added comment: Comment on list classification: Limited evidence for green rating. Should be reviewed at the next major review of this panel.
Monogenic hearing loss v2.65 SOX2 Eleanor Williams Gene: sox2 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.64 SOX2 Eleanor Williams Publications for gene: SOX2 were set to PMID:10564870; 11135495; 12002146; 12036291; 12461687; 12612584; 14517545; 15240551; 15346919; 15389708; 15812812; 15846349; 16145681; 16283891; 16470798; 16543359; 16651659; 16712695; 16892407; 16904174; 16932809; 17015430; 17219395; 17515932; 17522155; 17554336; 17554338; 18029452; 18157115; 18285410; 18385377; 18806776; 18818365; 18831064; 18845712; 19254784; 19403656; 19801978; 19898493; 19921648; 20803647; 21326281; 21331042; 21532573; 21919124; 24048479; 24909994; 7849401; 8741917
Monogenic hearing loss v2.63 SOX2 Eleanor Williams edited their review of gene: SOX2: Changed rating: AMBER
Monogenic hearing loss v2.63 SOX2 Eleanor Williams commented on gene: SOX2
Paroxysmal central nervous system disorders v1.4 CSNK1D Zornitza Stark reviewed gene: CSNK1D: Rating: AMBER; Mode of pathogenicity: None; Publications: 15800623, 23636092; Phenotypes: Advanced sleep-phase syndrome, familial, 2 615224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.51 XK Zornitza Stark gene: XK was added
gene: XK was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
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
Phenotypes for gene: XK were set to McLeod syndrome with or without chronic granulomatous disease MIM#300842
Review for gene: XK was set to GREEN
gene: XK was marked as current diagnostic
Added comment: 5 out of 13 cases had dystonia as a feature of the condition.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 UBTF Zornitza Stark gene: UBTF was added
gene: UBTF was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: UBTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBTF were set to 28777933; 29300972
Phenotypes for gene: UBTF were set to Neurodegeneration, childhood-onset, with brain atrophy MIM#617672
Mode of pathogenicity for gene: UBTF 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: UBTF was set to GREEN
gene: UBTF was marked as current diagnostic
Added comment: 7 out of 11 unrelated cases with a recurrent de novo gain of function missense variant (p.Glu210Lys) have dystonia as a feature of the condition.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 TBC1D24 Zornitza Stark gene: TBC1D24 was added
gene: TBC1D24 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: TBC1D24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D24 were set to 31257402
Phenotypes for gene: TBC1D24 were set to Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp, MIM# 608105
Review for gene: TBC1D24 was set to GREEN
Added comment: Three unrelated families reported with rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC), an autosomal recessive neurologic disorder characterised by onset of focal seizures in infancy and exercise-induced dystonia in childhood. Features usually include involuntary movements, including facial movements, and difficulties with fine motor skills of the hand. Seizures often respond to medication and remit with age; the dystonia tends to persist. Three unrelated families reported with this specific phenotype, though variants in this gene are associated with a range of other neurological disorders and may represent a spectrum of severity.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 SYT1 Zornitza Stark gene: SYT1 was added
gene: SYT1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYT1 were set to 30107533
Phenotypes for gene: SYT1 were set to Baker-Gordon syndrome MIM#618218
Review for gene: SYT1 was set to GREEN
gene: SYT1 was marked as current diagnostic
Added comment: 4 out of 11 individuals with a de novo variant had dystonia as a feature of the phenotype.
Sources: Expert list
Fetal anomalies v1.95 ASXL3 Rhiannon Mellis reviewed gene: ASXL3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29316359; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Laterality disorders and isomerism v1.19 FOXJ1 Zornitza Stark changed review comment from: PMID 31630787 - Six unrelated individuals with de novo variants in this gene. Patients have hydrocephaly, bronchiectasis and respiratory disease. Situs inversus was shown in 3/6 patients.
Electron microscopy of demonstrated cilia were unable to general fluid flow and were less frequent on cells. All reported variants were truncating mutations affecting the last exon in the protein, therefore loss of function is less likely the mechanism of pathogenicity
Sources: Expert list; to: PMID 31630787 - Six unrelated individuals with de novo variants in this gene. Patients have hydrocephaly, bronchiectasis and respiratory disease. Situs inversus was shown in 3/6 patients.
Electron microscopy demonstrated cilia were unable to generate fluid flow and were less frequent on cells. All reported variants were truncating mutations affecting the last exon in the protein, therefore loss of function is less likely the mechanism of pathogenicity
Sources: Expert list
Monogenic hearing loss v2.63 TOP2B Zornitza Stark edited their review of gene: TOP2B: Changed rating: AMBER
Monogenic hearing loss v2.63 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed rating: AMBER
Dystonia, chorea or related movement disorder, childhood onset v1.51 SQSTM1 Zornitza Stark changed review comment from: PMID: 27545679 - 9 patients (4 families) with childhood/adolescent onset neurodegeneration syndrome. 7/9 patients presented with dystonia. None noted to have myopathy.
Sources: Expert list; to: PMID: 27545679 - 9 patients (4 families) with childhood/adolescent onset neurodegeneration syndrome. 7/9 patients presented with dystonia.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 SQSTM1 Zornitza Stark edited their review of gene: SQSTM1: Changed phenotypes: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145
Dystonia, chorea or related movement disorder, childhood onset v1.51 SQSTM1 Zornitza Stark gene: SQSTM1 was added
gene: SQSTM1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SQSTM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQSTM1 were set to 27545679
Phenotypes for gene: SQSTM1 were set to Myopathy, distal, with rimmed vacuoles , MIM#617158
Review for gene: SQSTM1 was set to GREEN
Added comment: PMID: 27545679 - 9 patients (4 families) with childhood/adolescent onset neurodegeneration syndrome. 7/9 patients presented with dystonia. None noted to have myopathy.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 SNORD118 Zornitza Stark gene: SNORD118 was added
gene: SNORD118 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SNORD118 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNORD118 were set to 27571260
Phenotypes for gene: SNORD118 were set to Leukoencephalopathy, brain calcifications, and cysts MIM#614561
Review for gene: SNORD118 was set to GREEN
Added comment: At least 6 cases/families reported with dystonia as a feature of the condition.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 SLC16A2 Zornitza Stark gene: SLC16A2 was added
gene: SLC16A2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SLC16A2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SLC16A2 were set to 31410843
Phenotypes for gene: SLC16A2 were set to Allan-Herndon-Dudley syndrome, MIM# 300523
Review for gene: SLC16A2 was set to GREEN
gene: SLC16A2 was marked as current diagnostic
Added comment: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability. In a recent review of 24 affected individuals (PMID 31410843), 16 presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.51 PRNP Zornitza Stark reviewed gene: PRNP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Huntington disease-like 1, MIM# 603218; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.95 B9D2 Rhiannon Mellis gene: B9D2 was added
gene: B9D2 was added to Fetal anomalies. Sources: Literature,NHS GMS
Mode of inheritance for gene: B9D2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B9D2 were set to PMID: 21763481; 26092869
Phenotypes for gene: B9D2 were set to Joubert syndrome; Meckel syndrome
Review for gene: B9D2 was set to GREEN
gene: B9D2 was marked as current diagnostic
Added comment: 2 fetuses with MKS in one consanguineous family with homozygous B9D2 pathogenic variants. Functional studies of the variant confirmed loss of function. (PMID: 21763481)
2 unrelated patients with Joubert syndrome with different compound het B9D2 variants. (PMID: 26092869)

NB: Currently Green in ciliopathies panels. We report variants in this gene on our postnatal ciliopathies panel at GOSH/NTGLH.
Sources: Literature, NHS GMS
Fetal anomalies v1.95 B9D1 Rhiannon Mellis reviewed gene: B9D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32622957, 24886560; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.95 TMEM107 Rhiannon Mellis gene: TMEM107 was added
gene: TMEM107 was added to Fetal anomalies. Sources: Literature,NHS GMS
Mode of inheritance for gene: TMEM107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM107 were set to PMID: 26123494; 26518474; 26595381
Phenotypes for gene: TMEM107 were set to ?Joubert syndrome 29; Meckel syndrome 13; Orofaciodigital syndrome XVI
Review for gene: TMEM107 was set to GREEN
gene: TMEM107 was marked as current diagnostic
Added comment: 2 unrelated infants, born of consanguineous Saudi parents, with Meckel syndrome-13 (PMID: 26123494)
1 patient with oro-facio-digital syndrome, and a mouse model with ciliopathy phenotype (PMID: 26518474)
1 man with Jouberts syndrome and female twins (from an unrelated family) with orofaciodigital syndrome. Additional functional studies. (PMID: 26595381)

NB: Currently Green on rare multisystem/renal/neurological ciliopathies panels. We report variants in this gene on our postnatal ciliopathies panel at GOSH/NTGLH
Sources: Literature, NHS GMS
Fetal anomalies v1.95 TMEM216 Rhiannon Mellis reviewed gene: TMEM216: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20036350, 20512146; Phenotypes: Joubert syndrome, Meckel syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.95 KIF14 Rhiannon Mellis gene: KIF14 was added
gene: KIF14 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to PMID: 24128419; 30388224; 28892560; 29343805
Phenotypes for gene: KIF14 were set to ?Meckel syndrome 12; Microcephaly 20, primary
Review for gene: KIF14 was set to GREEN
gene: KIF14 was marked as current diagnostic
Added comment: Two fetuses in one family with complex multiple congenital anomalies consistent with ciliopathy phenotype. (PMID: 24128419)
Four more families with fetuses with similar phenotype (microcephaly, brain malformations and renal agenesis or hypodysplasia). Also functional (zebrafish) studies. Authors conclude that LOF variants cause the above syndromic phenotype while hypomorphic variants cause microcephaly without kidney defects. (PMID: 30388224)

Four unrelated families with AR primary microcephaly and biallelic KIF14 pathogenic variants (PMID: 28892560)
Four more unrelated families with AR primary microcephaly and biallelic KIF14 pathogenic variants. Two sibs from one of the families were fetuses with severe microcephaly detected prenatally and leading to termination of pregnancy. (PMID: 29343805)
Sources: Literature
Monogenic hearing loss v2.63 SPATC1L Eleanor Williams Classified gene: SPATC1L as Amber List (moderate evidence)
Monogenic hearing loss v2.63 SPATC1L Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 3 cases reported but only one with segregation data.
Monogenic hearing loss v2.63 SPATC1L Eleanor Williams Gene: spatc1l has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.62 SPATC1L Eleanor Williams Added comment: Comment on mode of inheritance: I am not sure from the publication about the mode of inheritance. I read it that each family had one variant (no compound hets) and therefore the mode of inheritance would be mono-allelic. However, leaving as both monallelic and biallelic for now due to expert review.
Monogenic hearing loss v2.62 SPATC1L Eleanor Williams Mode of inheritance for gene: SPATC1L was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.61 SPATC1L Eleanor Williams reviewed gene: SPATC1L: Rating: AMBER; Mode of pathogenicity: None; Publications: 30177775; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.61 SPNS2 Eleanor Williams Classified gene: SPNS2 as Amber List (moderate evidence)
Monogenic hearing loss v2.61 SPNS2 Eleanor Williams Added comment: Comment on list classification: Updating the rating from grey to amber. 1 reported case plus mouse model.
Monogenic hearing loss v2.61 SPNS2 Eleanor Williams Gene: spns2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.60 SPNS2 Eleanor Williams reviewed gene: SPNS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30973865, 25356849; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.51 SLC18A2 Zornitza Stark reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23363473, 31240161, 26497564; Phenotypes: Parkinsonism-dystonia, infantile, 2, MIM# 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.95 SLC20A1 Zornitza Stark gene: SLC20A1 was added
gene: SLC20A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC20A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC20A1 were set to 32850778; 27013921
Phenotypes for gene: SLC20A1 were set to Bladder-Exstrophy-Epispadias Complex (BEEC)
Review for gene: SLC20A1 was set to GREEN
gene: SLC20A1 was marked as current diagnostic
Added comment: Three individuals and animal model supporting role of this gene in urinary tract and urorectal development. We have included on our CAKUT panel.
Sources: Literature
Intellectual disability v3.295 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: Four additional individuals with dystonia, dysmorphism, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia, and neonatal onset. All had de novo missense variants. All are described to have global developmental delay, hence supporting upgrade in rating on this panel.; Changed rating: GREEN; Changed publications: https://doi.org/10.1212/NXG.0000000000000466; Changed phenotypes: Alternating hemiplegia of childhood 2, MIM#614820, Neurodevelopmental disorder; Set current diagnostic: yes
Intellectual disability v3.295 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
gene: WASHC4 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Literature
Intellectual disability v3.295 RAD50 Zornitza Stark reviewed gene: RAD50: Rating: AMBER; Mode of pathogenicity: None; Publications: 32212377; Phenotypes: Nijmegen breakage syndrome-like disorder, MIM# 613078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.21 RAD50 Zornitza Stark gene: RAD50 was added
gene: RAD50 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD50 were set to 19409520; 32212377
Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078
Review for gene: RAD50 was set to GREEN
gene: RAD50 was marked as current diagnostic
Added comment: Two individuals reported with bi-allelic variants in this gene showing dysmorphic facial features similar to NBS, short stature, microcephaly, and mild/moderate intellectual disability. Fibroblasts established from one of the individuals showed chromosomal instability and abnormal radioresistant DNA synthesis. The MRE11/RAD50/NBN (MRN) complex is involved in signaling processes inducing the repair of DNA double-strand breaks. Variants in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)‐like disorder, respectively, so this gene is a strong biological candidate for this phenotype.
Sources: Literature
Congenital myopathy v2.5 SVIL Zornitza Stark gene: SVIL was added
gene: SVIL was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVIL were set to 32779703
Phenotypes for gene: SVIL were set to Myopathy
Review for gene: SVIL was set to AMBER
Added comment: Four individuals from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.
Sources: Literature
Monogenic hearing loss v2.60 TMTC2 Eleanor Williams Classified gene: TMTC2 as Amber List (moderate evidence)
Monogenic hearing loss v2.60 TMTC2 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. Two families reported. Same variant in each. Both northern european decent.
Monogenic hearing loss v2.60 TMTC2 Eleanor Williams Gene: tmtc2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.59 TMTC2 Eleanor Williams Phenotypes for gene: TMTC2 were changed from Deafness to Deafness; Sensorineural hearing loss
Monogenic hearing loss v2.58 TMTC2 Eleanor Williams Added comment: Comment on mode of inheritance: Changing to imprinted status unknown. In one family the trait had been passed through the maternal side for two generations, but more evidence needed before saying paternally imprinted.
Monogenic hearing loss v2.58 TMTC2 Eleanor Williams Mode of inheritance for gene: TMTC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.57 TMTC2 Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM.

PMID: 29671961- Guillen‐Ahlers et al 2018 - report a mother and son with of Northern European descent (mother and son) with Sensorineural hearing loss were found by exome sequencing to share a variant (rs35725509, missense variant) in the TMTC2 gene. This variant showed a minor allele frequency below 1% in 2,203 individuals of European American (EA) ancestry (NHLBI GO Exome Sequencing Project.


PMID: 27311106 - Runge et al 2016 - report a large multigenerational Northern European family in which 9 family members had bilateral, symmetric, progressive Sensorineural hearing loss that reached severe to profound loss in childhood. Using exome sequencing and linkage and association analyses they identified a fully penetrant sequence variant (rs35725509) in the TMTC2 gene region. The variant segregates with SNHL in the family. However, the mutation is found in a relatively high percentage of individuals of Northern European descent in the 1000 Genomes and Exome Sequencing (http://evs.gs.washington.edu/EVS/) European call sets (1% and 0.8%, respectively).; to: Not associated with a phenotype in OMIM.

PMID: 29671961- Guillen‐Ahlers et al 2018 - report a mother and son with of Northern European descent (mother and son) with Sensorineural hearing loss were found by exome sequencing to share a variant (rs35725509, missense variant) in the TMTC2 gene. This variant showed a minor allele frequency below 1% in 2,203 individuals of European American (EA) ancestry (NHLBI GO Exome Sequencing Project. In two generations, the trait has been passed through the maternal side


PMID: 27311106 - Runge et al 2016 - report a large multigenerational Northern European family in which 9 family members had bilateral, symmetric, progressive Sensorineural hearing loss that reached severe to profound loss in childhood. Using exome sequencing and linkage and association analyses they identified a fully penetrant sequence variant (rs35725509) in the TMTC2 gene region. The variant segregates with SNHL in the family. However, the mutation is found in a relatively high percentage of individuals of Northern European descent in the 1000 Genomes and Exome Sequencing (http://evs.gs.washington.edu/EVS/) European call sets (1% and 0.8%, respectively).
Monogenic hearing loss v2.57 TMTC2 Eleanor Williams edited their review of gene: TMTC2: Changed rating: AMBER; Changed publications: 29671961, 27311106; Changed phenotypes: Sensorineural hearing loss; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.57 TMTC2 Eleanor Williams commented on gene: TMTC2
Neurodegenerative disorders, adult onset v2.16 DNAJC7 Zornitza Stark gene: DNAJC7 was added
gene: DNAJC7 was added to Neurodegenerative disorders - adult onset. Sources: Literature
Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNAJC7 were set to https://doi.org/10.1212/NXG.0000000000000503
Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis
Review for gene: DNAJC7 was set to AMBER
Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. No segregation or functional data. A small number of individuals with LOF variants are present in gnomad albeit less than expected. Given these are cohort studies, and an adult-onset condition, potentially of variable penetrance, we have taken a cautious approach and rated Amber for now but would be interested in other expert opinions. No PMID yet.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 TET2 Zornitza Stark reviewed gene: TET2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32518946; Phenotypes: Immune dysregulation, Lymphoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital myopathy v2.5 DHX16 Zornitza Stark gene: DHX16 was added
gene: DHX16 was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, MIM# 618733
Review for gene: DHX16 was set to AMBER
gene: DHX16 was marked as current diagnostic
Added comment: This gene is somewhat difficult to place on the right panels.

Overall, there are four unrelated individuals reported with de novo missense variants. Three of the individuals died in infancy, so phenotypic information is limited, though hypotonia was prominent. Two had seizures. Individual with long-term survival had a progressive course, evidence of neuropathy, myopathy, loss of hearing and vision, and normal IQ.
Sources: Literature
Monogenic hearing loss v2.57 TOP2B Eleanor Williams Phenotypes for gene: TOP2B were changed from Deafness, autosomal dominant to Deafness, autosomal dominant; nonsyndromic hearing loss
Monogenic hearing loss v2.56 TOP2B Eleanor Williams Classified gene: TOP2B as Amber List (moderate evidence)
Monogenic hearing loss v2.56 TOP2B Eleanor Williams Added comment: Comment on list classification: Changing the rating from grey to amber. 1 familial case plus 3 sporadic cases reported. Supportive animal model. All reported in one publication so will wait until there is an additional supporting familial case before rating green.
Monogenic hearing loss v2.56 TOP2B Eleanor Williams Gene: top2b has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.55 TOP2B Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM.

PMID: 31198993 - Xia et al 2019 - Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. A variant in TOP2B (c.G4837C:p.D1613H) segregated with hearing loss in this family. Two variants other of TOP2B were detected in 66 sporadic patients with hearing loss. In zebrafish, top2b knockdown led to defects in the inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling.; to: Not associated with a phenotype in OMIM.

PMID: 31198993 - Xia et al 2019 - Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. A variant in TOP2B (c.G4837C:p.D1613H) segregated with hearing loss in this family. Two other variants of TOP2B were detected in 66 sporadic patients with hearing loss (p.L721F and p. K1435del, plus another case with p.D1613H). In zebrafish, top2b knockdown led to defects in the inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling.
Monogenic hearing loss v2.55 TOP2B Eleanor Williams reviewed gene: TOP2B: Rating: AMBER; Mode of pathogenicity: None; Publications: 31198993; Phenotypes: nonsyndromic hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.55 WBP2 Eleanor Williams Phenotypes for gene: WBP2 were changed from Deafness, autosomal recessive 107, MIM#617639 to Deafness, autosomal recessive 107, 617639
Monogenic hearing loss v2.54 WBP2 Eleanor Williams Classified gene: WBP2 as Amber List (moderate evidence)
Monogenic hearing loss v2.54 WBP2 Eleanor Williams Added comment: Comment on list classification: Changing the rating from grey to Amber. 2 cases plus mouse model but all from one paper. No further evidence since 2016.
Monogenic hearing loss v2.54 WBP2 Eleanor Williams Gene: wbp2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.53 WBP2 Eleanor Williams edited their review of gene: WBP2: Changed rating: AMBER; Changed publications: 26881968; Changed phenotypes: Deafness, autosomal recessive 107 617639; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.53 WBP2 Eleanor Williams commented on gene: WBP2
Monogenic hearing loss v2.53 FDXR Eleanor Williams edited their review of gene: FDXR: Changed rating: GREEN
Monogenic hearing loss v2.53 FDXR Eleanor Williams Tag for-review tag was added to gene: FDXR.
Monogenic hearing loss v2.53 FDXR Eleanor Williams changed review comment from: Comment on list classification: There are 3 cases where hearing loss is reported as the first symptom, although there are other cases in which variants in this gene do not result in hearing loss, or hearing loss after an optic phenotype.; to: Comment on list classification: There are 3 cases where hearing loss is reported as the first symptom, although there are other cases in which variants in this gene do not result in hearing loss, or hearing loss after an optic phenotype. Rating amber for now until this gene can be reviewed by the GMS.
Monogenic hearing loss v2.53 FDXR Eleanor Williams Classified gene: FDXR as Amber List (moderate evidence)
Monogenic hearing loss v2.53 FDXR Eleanor Williams Added comment: Comment on list classification: There are 3 cases where hearing loss is reported as the first symptom, although there are other cases in which variants in this gene do not result in hearing loss, or hearing loss after an optic phenotype.
Monogenic hearing loss v2.53 FDXR Eleanor Williams Gene: fdxr has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.52 FDXR Eleanor Williams changed review comment from: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.

PMID: 29040572 (Peng et al 2017) - report 17 individuals from 13 unrelated families with recessive mutations in FDXR. The core clinical features were optic atrophy, ataxia, and hypotonia but hearing loss was also noted as a less common phenotype.

Note, other cases reported with variants FDXR but no hearing loss phenotype e.g. PMID: 30250212 (Slone et al, 2018) ; to: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals from 3 families hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.

PMID: 29040572 (Peng et al 2017) - report 17 individuals from 13 unrelated families with recessive mutations in FDXR. The core clinical features were optic atrophy, ataxia, and hypotonia but hearing loss was also noted as a less common phenotype.

Note, other cases reported with variants FDXR but no hearing loss phenotype e.g. PMID: 30250212 (Slone et al, 2018)
Monogenic hearing loss v2.52 FDXR Eleanor Williams changed review comment from: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.; to: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.

PMID: 29040572 (Peng et al 2017) - report 17 individuals from 13 unrelated families with recessive mutations in FDXR. The core clinical features were optic atrophy, ataxia, and hypotonia but hearing loss was also noted as a less common phenotype.

Note, other cases reported with variants FDXR but no hearing loss phenotype e.g. PMID: 30250212 (Slone et al, 2018)
Intellectual disability v3.295 ATP1A2 Sarah Leigh commented on gene: ATP1A2: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.295 ATP1A2 Sarah Leigh Tag for-review tag was added to gene: ATP1A2.
Intellectual disability v3.295 ATP1A2 Sarah Leigh edited their review of gene: ATP1A2: Added comment: Associated with phenotype in OMIM and in G2P for MIGRAINE, FAMILIAL HEMIPLEGIC, ATP1A2-related. Three variants associated with congnitive impairment in 2/7 and 1/5 members of two families with Migraine, familial hemiplegic, 2 602481. At least 12 variants have been reported in Migraine, familial hemiplegic, 2 602481 families (PMID 15159495). An additional variant was reported in a case of Alternating hemiplegia of childhood 1, 104290 with impared cognitive function (PMID 29610157).; Changed rating: GREEN
Intellectual disability v3.295 ANKH Sarah Leigh commented on gene: ANKH: There is no evidence for this gene to be rated GREEN, it should be rated RED at the next major review.
Intellectual disability v3.295 ANKH Sarah Leigh reviewed gene: ANKH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.295 ANKH Sarah Leigh Publications for gene: ANKH were set to
Intellectual disability v3.294 ANKH Sarah Leigh Tag for-review tag was added to gene: ANKH.
Intellectual disability v3.294 TNR Arina Puzriakova Classified gene: TNR as Amber List (moderate evidence)
Intellectual disability v3.294 TNR Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.
Intellectual disability v3.294 TNR Arina Puzriakova Gene: tnr has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.293 TNR Arina Puzriakova reviewed gene: TNR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22730557, 32099069; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.52 FDXR Eleanor Williams reviewed gene: FDXR: Rating: ; Mode of pathogenicity: None; Publications: 28965846; Phenotypes: Auditory neuropathy and optic atrophy 617717; Mode of inheritance: None
Monogenic hearing loss v2.52 CISD2 Eleanor Williams Tag for-review tag was added to gene: CISD2.
Monogenic hearing loss v2.52 CISD2 Eleanor Williams Classified gene: CISD2 as Amber List (moderate evidence)
Monogenic hearing loss v2.52 CISD2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber as several cases reported with hearing loss as a feature, but not as the first presenting feature.
Monogenic hearing loss v2.52 CISD2 Eleanor Williams Gene: cisd2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.51 CISD2 Eleanor Williams Phenotypes for gene: CISD2 were changed from hearing loss to hearing loss; Wolfram syndrome 2 604928
Monogenic hearing loss v2.50 CISD2 Eleanor Williams Publications for gene: CISD2 were set to
Monogenic hearing loss v2.49 CISD2 Eleanor Williams edited their review of gene: CISD2: Changed rating: AMBER; Changed publications: 10739754, 17846994, 25056293, 25371195; Changed phenotypes: Wolfram syndrome 2 #604928; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.49 CISD2 Eleanor Williams commented on gene: CISD2
Intellectual disability v3.293 EARS2 Sarah Leigh Tag for-review tag was added to gene: EARS2.
Intellectual disability v3.293 EARS2 Sarah Leigh edited their review of gene: EARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.293 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.293 EARS2 Sarah Leigh Publications for gene: EARS2 were set to 22492562
Intellectual disability v3.292 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Classified gene: EARS2 as Amber List (moderate evidence)
Intellectual disability v3.292 EARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Gene: ears2 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.9 ALPK3 Ivone Leong Phenotypes for gene: ALPK3 were changed from Hypertrophic cardiomyopathy to Cardiomyopathy, familial hypertrophic 27, 618052
Paediatric or syndromic cardiomyopathy v1.7 MRAS Ivone Leong Classified gene: MRAS as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.7 MRAS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is also Green on the RASopathies panel (v 1.61).

Review copied from RASopathies panel:
"Associated with Noonan syndrome in OMIM and G2P (confirmed). PMID: 28289718 (2017) - In two unrelated patients with Noonan syndrome and cardiac hypertrophy, trio WES/targeted sequencing revealed de novo missense variants (c.68G>T, p.G23V and c.203C>T, p.T68I) in the MRAS gene. Functional studies of the p.Gly23Val variant showed the change yields a constitutively active form of MRAS.

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

PMID: 31108500 (2020) - Two unrelated patients with Noonan syndrome, including hypertrophic cardiomyopathy and dysmorphic features. Targeted sequencing revealed de novo activating MRAS variants (c.203C>T, p.T68I and c.67G>C, p.G23R). Functional studies demonstrated that the variants yields a constitutively active form of MRAS.
Arina Puzriakova (Genomics England Curator), 4 Aug 2020"

Therefore, this gene will be promoted to Green status at the next major review.
Paediatric or syndromic cardiomyopathy v1.7 MRAS Ivone Leong Gene: mras has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.6 MRAS Ivone Leong Tag for-review tag was added to gene: MRAS.
Monogenic hearing loss v2.49 SLC12A2 Arina Puzriakova Phenotypes for gene: SLC12A2 were changed from to Bilateral sensorineural hearing loss; Intellectual disability; Secretory defects
Monogenic hearing loss v2.48 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to
Monogenic hearing loss v2.47 SLC12A2 Arina Puzriakova Mode of inheritance for gene: SLC12A2 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.46 SLC12A2 Arina Puzriakova Classified gene: SLC12A2 as Amber List (moderate evidence)
Monogenic hearing loss v2.46 SLC12A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 10 unrelated cases (and animal models) presenting significant sensorineural hearing loss, associated with variants in SLC12A2.
Monogenic hearing loss v2.46 SLC12A2 Arina Puzriakova Gene: slc12a2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.45 SLC12A2 Arina Puzriakova Tag for-review tag was added to gene: SLC12A2.
Monogenic hearing loss v2.45 SLC12A2 Arina Puzriakova reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30740830, 32294086, 32754646, 32658972; Phenotypes: Bilateral sensorineural hearing loss, Intellectual disability, Secretory defects; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.6 MRAS Ivone Leong Phenotypes for gene: MRAS were changed from Noonan syndrome, MIM#618499 to Noonan syndrome, 618499
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Tag watchlist tag was added to gene: DNAH6.
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Classified gene: DNAH6 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Based on the evidence there is not enough evidence to support a gene-disease association. This gene has been given an Amber gene rating until further evidence is available.
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Gene: dnah6 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.18 FOXJ1 Ivone Leong Classified gene: FOXJ1 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.18 FOXJ1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There are enough cases to support a gene-disease association. There are also several animal models (PMID: 9739041, 15504371) that show that this gene has a role in L-R body assymmetry determination during early embryogenesis. This gene will be upgraded to Green status at the next major update.
Laterality disorders and isomerism v1.18 FOXJ1 Ivone Leong Gene: foxj1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.17 FOXJ1 Ivone Leong Tag for-review tag was added to gene: FOXJ1.
Intellectual disability v3.291 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to 28940097; 30740830; 32754646
Intellectual disability v3.290 SLC12A2 Arina Puzriakova Mode of inheritance for gene: SLC12A2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.17 FOXJ1 Ivone Leong Publications for gene: FOXJ1 were set to 31630787
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.; to: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least nine unrelated cases presenting a relevant phenotype in association with variants in SLC12A2.
Intellectual disability v3.289 SLC12A2 Arina Puzriakova edited their review of gene: SLC12A2: Changed publications: 28940097, 30740830, 32754646, 32658972; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.; to: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.

- PMID: 32658972 (2020) - Six unrelated children, all with mild-severe ID/DD, associated with de novo variants in SLC12A2. Additional clinical features included bilateral sensorineural hearing loss (2/6), abnormalities on brain MRI (2/4), and cerebral palsy (2/6). Some functional data in Xenopus laevis oocytes, indicating a role of SLC12A2 in neurogenesis.
Laterality disorders and isomerism v1.16 PKD1L1 Ivone Leong reviewed gene: PKD1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.16 PKD1L1 Ivone Leong Tag for-review tag was added to gene: PKD1L1.
Laterality disorders and isomerism v1.16 PKD1L1 Ivone Leong Publications for gene: PKD1L1 were set to 31026592; 27616478
Laterality disorders and isomerism v1.15 PKD1L1 Ivone Leong Mode of inheritance for gene: PKD1L1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.14 PKD1L1 Ivone Leong Publications for gene: PKD1L1 were set to 31026592
Laterality disorders and isomerism v1.13 PKD1L1 Ivone Leong Publications for gene: PKD1L1 were set to
Laterality disorders and isomerism v1.12 PKD1L1 Ivone Leong Phenotypes for gene: PKD1L1 were changed from to Heterotaxy, visceral, 8, autosomal, 617205
Intellectual disability v3.289 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX37 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to 26539891; 31256877
Phenotypes for gene: DHX37 were set to Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Review for gene: DHX37 was set to GREEN
gene: DHX37 was marked as current diagnostic
Added comment: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic variants causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.
Sources: Literature
Fetal anomalies v1.95 TRPM7 Zornitza Stark gene: TRPM7 was added
gene: TRPM7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRPM7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPM7 were set to 32503408; 31423533
Phenotypes for gene: TRPM7 were set to Cardiac arrhythmia, stillbirth
Review for gene: TRPM7 was set to AMBER
Added comment: I am not sure if genes linked to stillbirth belong on this panel. This gene encodes an ion channel expressed in the nervous and cardiac systems. It has previously been associated with ALS/dementia in the Guam population, but the variant in question, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association.
Sources: Literature
Proteinuric renal disease v2.26 YRDC Zornitza Stark gene: YRDC was added
gene: YRDC was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: YRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YRDC were set to 31481669
Phenotypes for gene: YRDC were set to Galloway-Mowat syndrome
Review for gene: YRDC was set to GREEN
gene: YRDC was marked as current diagnostic
Added comment: Three individuals from two unrelated families with typical features of Galloway-Mowat syndrome including proteinuria, microcephaly, developmental delay and brain malformations. Supportive functional data.
Sources: Literature
Proteinuric renal disease v2.26 GON7 Zornitza Stark gene: GON7 was added
gene: GON7 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: GON7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON7 were set to 31481669
Phenotypes for gene: GON7 were set to Galloway-Mowat syndrome
Review for gene: GON7 was set to GREEN
gene: GON7 was marked as current diagnostic
Added comment: 11 individuals from 5 families. Four of the families had the same homozygous variant, shared haplotype suggestive of founder effect. Clinical features included proteinuria, microcephaly, brain malformations and developmental delay. Supportive functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 TLR7 Zornitza Stark gene: TLR7 was added
gene: TLR7 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TLR7 were set to 32706371
Phenotypes for gene: TLR7 were set to Immunodeficiency 74, COVID19-related, X-linked, MIM# 301051
Review for gene: TLR7 was set to GREEN
Added comment: Four affected individuals from two unrelated families and some functional data.
Sources: Literature
Mitochondrial disorders v2.8 NDUFA13 Zornitza Stark reviewed gene: NDUFA13: Rating: AMBER; Mode of pathogenicity: None; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.4 PDE2A Zornitza Stark reviewed gene: PDE2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32467598, 32196122, 29392776; Phenotypes: Paroxysmal dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital myopathy v2.5 MYOD1 Zornitza Stark gene: MYOD1 was added
gene: MYOD1 was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOD1 were set to 26733463; 30403323; 31260566
Phenotypes for gene: MYOD1 were set to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, MIM# 618975
Review for gene: MYOD1 was set to GREEN
gene: MYOD1 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.13 PSMC3 Zornitza Stark gene: PSMC3 was added
gene: PSMC3 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to Deafness; cataract
Review for gene: PSMC3 was set to AMBER
Added comment: Three affected individuals from a single consanguineous family reported with homozygous intronic variant. Gene-disease association is supported by an animal model.
Sources: Literature
Intellectual disability v3.289 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to 30740830
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Classified gene: SLC12A2 as Amber List (moderate evidence)
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Gene: slc12a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.287 SLC12A2 Arina Puzriakova Tag for-review tag was added to gene: SLC12A2.
Intellectual disability v3.287 SLC12A2 Arina Puzriakova reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Segmental overgrowth disorders - Deep sequencing v2.7 SUZ12 Sarah Leigh Classified gene: SUZ12 as Amber List (moderate evidence)
Segmental overgrowth disorders - Deep sequencing v2.7 SUZ12 Sarah Leigh Gene: suz12 has been classified as Amber List (Moderate Evidence).
Segmental overgrowth disorders - Deep sequencing v2.6 SUZ12 Sarah Leigh gene: SUZ12 was added
gene: SUZ12 was added to Segmental overgrowth disorders. Sources: Literature
for-review tags were added to gene: SUZ12.
Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUZ12 were set to 28229514; 30019515; 31736240; 15385962; 19535498; 31724824
Phenotypes for gene: SUZ12 were set to Imagawa-Matsumoto syndrome 618786
Review for gene: SUZ12 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families.
Sources: Literature
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.97 SUZ12 Sarah Leigh Classified gene: SUZ12 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.97 SUZ12 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.97 SUZ12 Sarah Leigh Gene: suz12 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.96 SUZ12 Sarah Leigh Phenotypes for gene: SUZ12 were changed from Imagawa-Matsumoto syndrome, MIM# 618786 to Imagawa-Matsumoto syndrome 618786
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.95 SUZ12 Sarah Leigh Publications for gene: SUZ12 were set to 31736240; 28229514
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Three patients from two unrelated families with myoclonic seizures, and additional focal epilepsy with versive head movement in one patient (onset at birth/6 months, respectively).

Additional unrelated cases required before inclusion on a diagnostic panel; and therefore, rating Amber in anticipation of further publications (added to watchlist).
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.149 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Early onset or syndromic epilepsy v2.149 EXOC7 Arina Puzriakova gene: EXOC7 was added
gene: EXOC7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to Brain atrophy; Seizures; Developmental delay; Microcephaly
Added comment: PMID: 32103185 (2020) - 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Literature
Intellectual disability v3.287 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Intellectual disability v3.287 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Though mild-severe DD is reported in all surviving patients to date (4 individuals from 2 families), additional unrelated cases required before inclusion on a diagnostic panel.

Therefore, rating Amber in anticipation of further publications (added to watchlist).
Intellectual disability v3.287 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Though mild microcephaly reported in 5/8 cases (-0.5 to -2.6 SD), rating Amber as severity of presentation is not within the scope of this panel.
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.286 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Dystonia, chorea or related movement disorder, childhood onset v1.51 HNRNPH1 Arina Puzriakova Tag for-review tag was added to gene: HNRNPH1.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Tag for-review tag was added to gene: HNRNPH1.
Dystonia, chorea or related movement disorder, childhood onset v1.51 HNRNPH1 Arina Puzriakova Classified gene: HNRNPH1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.51 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 6 unrelated cases with a movement phenotype.
Dystonia, chorea or related movement disorder, childhood onset v1.51 HNRNPH1 Arina Puzriakova Gene: hnrnph1 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.50 HNRNPH1 Arina Puzriakova gene: HNRNPH1 was added
gene: HNRNPH1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPH1 were set to 29938792; 32335897
Phenotypes for gene: HNRNPH1 were set to HNRNPH1-related neurodevelopmental disorder
Review for gene: HNRNPH1 was set to GREEN
Added comment: Probable gene for HNRNPH1-related neurodevelopmental disorder in G2P, but currently not associated with any phenotype in OMIM (last edited on 21/07/2017).

Two studies report de novo variants in 8 unrelated cases with a syndromic intellectual disability disorder. Clinical features included moderate-severe GDD/ID (7/7), abnormalities on brain MRI (8/8), ophthalmological abnormalities (7/8), short stature (6/8), and microcephaly (6/8). Movement manifestations were also observed - 3 individuals were non-ambulatory, while another 3 presented dystonia, one of whom also had ataxia, tremor, and wide‐based gait.
Sources: Literature
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova changed review comment from: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Classified gene: HNRNPH1 as Amber List (moderate evidence)
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Gene: hnrnph1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.12 HARS Arina Puzriakova commented on gene: HARS: Added new-gene-name tag, new approved HGNC gene symbol for HARS is HARS1
Ataxia and cerebellar anomalies - childhood onset v2.12 HARS Arina Puzriakova Tag new-gene-name tag was added to gene: HARS.
Ataxia and cerebellar anomalies - childhood onset v2.12 HARS Arina Puzriakova Classified gene: HARS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.12 HARS Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel but additional cases required. Therefore, rating Amber in anticipation of further publications.
Ataxia and cerebellar anomalies - childhood onset v2.12 HARS Arina Puzriakova Gene: hars has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.11 HARS Arina Puzriakova gene: HARS was added
gene: HARS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: HARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS were set to 32333447
Phenotypes for gene: HARS were set to Multisystem ataxic syndrome; Intellectual disability
Review for gene: HARS was set to AMBER
Added comment: PMID: 32333447 (2020) - Three individuals from two unrelated families harbouring biallelic HARS variants. Manifestations included microcephaly, mild‐to severe ID, skeletal deformities, and ataxic broad base gait with clinical features affecting the cerebellar and pyramidal tract system. Some supportive functional analysis of the variants in skin fibroblasts and yeast.
Sources: Literature
Intellectual disability v3.285 HARS Arina Puzriakova commented on gene: HARS: Added new-gene-name tag, new approved HGNC gene symbol for HARS is HARS1
Intellectual disability v3.285 HARS Arina Puzriakova Tag new-gene-name tag was added to gene: HARS.
Intellectual disability v3.285 HARS Arina Puzriakova Classified gene: HARS as Amber List (moderate evidence)
Intellectual disability v3.285 HARS Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel but additional cases required. Therefore, rating Amber in anticipation of further publications.
Intellectual disability v3.285 HARS Arina Puzriakova Gene: hars has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.95 GDF2 Zornitza Stark gene: GDF2 was added
gene: GDF2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GDF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GDF2 were set to 32618121
Phenotypes for gene: GDF2 were set to Lymphatic dysplasia; hydrothorax; hydrops
Review for gene: GDF2 was set to RED
Added comment: Single family reported, two affected individuals. New MOI.

Monoallelic variants in this gene are associated with HHT/PAH.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.10 EXOSC5 Arina Puzriakova changed review comment from: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature; to: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.10 EXOSC5 Arina Puzriakova Classified gene: EXOSC5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.10 EXOSC5 Arina Puzriakova Added comment: Comment on list classification: Three unrelated families presenting ataxia in association with cerebellar hypoplasia/atrophy. However, all harbour the same p.Thr114Ile variant, and thus it is unclear whether other EXOSC5 variants result in cerebellar ataxia.

Therefore, rating Amber in anticipation of additional publications/clinical evidence.
Ataxia and cerebellar anomalies - childhood onset v2.10 EXOSC5 Arina Puzriakova Gene: exosc5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.9 EXOSC5 Arina Puzriakova Publications for gene: EXOSC5 were set to 32504085
Ataxia and cerebellar anomalies - childhood onset v2.8 EXOSC5 Arina Puzriakova edited their review of gene: EXOSC5: Changed publications: 32504085, 29302074
Ataxia and cerebellar anomalies - childhood onset v2.8 EXOSC5 Arina Puzriakova gene: EXOSC5 was added
gene: EXOSC5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: EXOSC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC5 were set to 32504085
Phenotypes for gene: EXOSC5 were set to Short stature; Motor developmental delays; Cerebellar hypoplasia; Ataxia
Added comment: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.49 PDGFB Zornitza Stark reviewed gene: PDGFB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Basal ganglia calcification, idiopathic, 4 615007; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.49 OCLN Zornitza Stark reviewed gene: OCLN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudo-TORCH syndrome 1, MIM# 251290; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.49 L2HGDH Zornitza Stark reviewed gene: L2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753671, 18780161, 15824270, 10399870; Phenotypes: L-2-hydroxyglutaric aciduria MIM#236792; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Dystonia, chorea or related movement disorder, childhood onset v1.49 KCNQ2 Zornitza Stark reviewed gene: KCNQ2: Rating: RED; Mode of pathogenicity: None; Publications: 12742592; Phenotypes: Epileptic encephalopathy, early infantile, 7 MIM#613720; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.49 IRF2BPL Zornitza Stark gene: IRF2BPL was added
gene: IRF2BPL was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: IRF2BPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF2BPL were set to 30057031; 30166628
Phenotypes for gene: IRF2BPL were set to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088
Review for gene: IRF2BPL was set to GREEN
gene: IRF2BPL was marked as current diagnostic
Added comment: PMID: 30057031 - 7 individuals with neurodevelopmental regression (5/7), progressive ataxia (5/7), seizures (7/7), spasticity (2/7), dystonia (3/7) and global devel delay (7/7). PTCs produced a more severe phenotype than missense. Onset was in childhood. Cerebellar changes also less frequently reported.

PMID: 30166628 - 11 individuals with de novo PTCs with childhood neurological regression, epilepsy (7/11), hypotonia (5/11), dystonia (3/11), cerebellar atrophy (5/10). MRI showed CNS defects in 6/10 patients.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.49 HPRT1 Zornitza Stark reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301328; Phenotypes: Lesch-Nyhan syndrome, MIM# 300322; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, childhood onset v1.49 GRIN1 Zornitza Stark gene: GRIN1 was added
gene: GRIN1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: GRIN1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GRIN1 were set to 29365063; 27164704; 27164704; 28051072
Phenotypes for gene: GRIN1 were set to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Review for gene: GRIN1 was set to GREEN
gene: GRIN1 was marked as current diagnostic
Added comment: Over 20 individuals reported with de novo missense variants in GRIN1 and severe neurodevelopmental phenotype, comprising ID, seizures, and a movement disorder, in particular dystonia. Two families reported with bi-allelic variants: different mechanism postulated (LOF vs affecting channel functioning or hypomorphic alleles), parents were carriers and unaffected. Movement disorder, in particular dystonia also reported in bi-allelic cases.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.49 GNB1 Zornitza Stark gene: GNB1 was added
gene: GNB1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: GNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNB1 were set to 27108799; 30194818; 27668284; 31034681
Phenotypes for gene: GNB1 were set to Mental retardation, autosomal dominant 42, MIM# 616973
Review for gene: GNB1 was set to GREEN
gene: GNB1 was marked as current diagnostic
Added comment: Multiple reports of dystonia in this disorder. In a recent series of 18 individuals with de novo mutations, the most observed substitution affected the p.Ile80 residue in exon 6, with 28% of individuals carrying a variant at this residue. Dystonia and growth delay were observed more frequently in individuals carrying variants in this residue, suggesting a potential genotype-phenotype correlation.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.49 GLRB Zornitza Stark reviewed gene: GLRB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperekplexia 2, MIM# 614619; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.49 FXN Zornitza Stark reviewed gene: FXN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Friedreich ataxia, MIM# 229300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.49 FUCA1 Zornitza Stark reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31064022; Phenotypes: Fucosidosis, MIM#230000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.49 FOXG1 Zornitza Stark reviewed gene: FOXG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27029630; Phenotypes: Rett syndrome, congenital variant, MIM# 613454; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Dystonia, chorea or related movement disorder, childhood onset v1.49 FITM2 Zornitza Stark gene: FITM2 was added
gene: FITM2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: FITM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FITM2 were set to 28067622; 30214770; 30288795
Phenotypes for gene: FITM2 were set to Siddiqi syndrome MIM#618635; dystonia; deafness
Review for gene: FITM2 was set to GREEN
gene: FITM2 was marked as current diagnostic
Added comment: 7 cases from 3 unrelated families (2 consanguineous) with a dystonia-deafness syndrome and a supporting Drosophila model.
Sources: Expert list
Dystonia, chorea or related movement disorder, childhood onset v1.49 CSTB Zornitza Stark reviewed gene: CSTB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.49 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: 10762541, 9628818, 27003325; Phenotypes: Episodic ataxia, type 5, MIM#613855; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dystonia, chorea or related movement disorder, childhood onset v1.49 C9orf72 Zornitza Stark changed review comment from: Dystonia is well described but this appears to be an adult-onset disorder.; to: Dystonia is well described but this appears to be an adult-onset disorder. Also note condition is caused by heterozygous hexanucleotide repeat expansion (GGGGCC) in a noncoding region of the C9ORF72 gene.
Dystonia, chorea or related movement disorder, childhood onset v1.49 C9orf72 Zornitza Stark reviewed gene: C9orf72: Rating: RED; Mode of pathogenicity: None; Publications: 26166205, 24363131, 26187722; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, MIM# 105550; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.49 BCS1L Zornitza Stark reviewed gene: BCS1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.49 ALDH18A1 Zornitza Stark reviewed gene: ALDH18A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 9B, autosomal recessive, MIM# 616586, Spastic paraplegia 9A, autosomal dominant, MIM# 601162; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.49 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: 22964162, 16541453; Phenotypes: Spastic ataxia 5, autosomal recessive MIM#614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 YIF1B Zornitza Stark gene: YIF1B was added
gene: YIF1B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098; 26077767
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Review for gene: YIF1B was set to GREEN
gene: YIF1B was marked as current diagnostic
Added comment: 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.
Sources: Expert list
Severe microcephaly v2.20 UNC80 Zornitza Stark gene: UNC80 was added
gene: UNC80 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UNC80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC80 were set to 26708751; 26708753; 26545877; 29572195
Phenotypes for gene: UNC80 were set to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 MIM#616801
Review for gene: UNC80 was set to GREEN
gene: UNC80 was marked as current diagnostic
Added comment: Summary: Many patients reported as microcephalic. Not all have head circumference < -3SD but there are at least 3 unrelated individuals reported with head circumference smaller than this.

PMID 26708751: 4 individuals from 3 families reported. At 4 years one had OFC -4SD (the others 2nd centile at 4yo, 3rd centile at 15yo, and 10th centile at 9yo).

PMID 26708753: Two 'not directly related' families F1 and F2 identified with the same variant. A third and fourth family had different variants. All affected individuals described were microcephalic (F1: -3.2SD at 4yo; F2: -4SD at 2yo and -2.9SD at 13mo; F3: -2.4SD at 7yo; F4: 9th centile at 4yo and 5th centile at 8yo).

PMID 26545877: 7 affected individuals from 2 distantly related families with the same nonsense variant were all microcephalic (<2nd centile).

PMID 29572195: 2 unrelated individuals reported. Head circumference of patient 1 was -0.5SD at 9yo; Patient 2 -3.7SD at 3yo.
Sources: Expert list
Severe microcephaly v2.20 UGP2 Zornitza Stark gene: UGP2 was added
gene: UGP2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGP2 were set to 31820119
Phenotypes for gene: UGP2 were set to Epileptic encephalopathy; intellectual disability; microcephaly
Review for gene: UGP2 was set to GREEN
gene: UGP2 was marked as current diagnostic
Added comment: 22 individuals from 15 families reported with the same homozygous missense variant in this gene, chr2:64083454A > G, which causes a disruption of the start codon in the shorter isoform, which is expressed in brain.
Sources: Expert list
Severe microcephaly v2.20 UBE3A Zornitza Stark gene: UBE3A was added
gene: UBE3A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UBE3A was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Phenotypes for gene: UBE3A were set to Angelman syndrome MIM#105830
Review for gene: UBE3A was set to GREEN
gene: UBE3A was marked as current diagnostic
Added comment: Microcephaly is a key feature.
Sources: Expert list
Severe microcephaly v2.20 TSEN54 Zornitza Stark gene: TSEN54 was added
gene: TSEN54 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TSEN54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN54 were set to 20952379; 20301773
Phenotypes for gene: TSEN54 were set to Pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753)
Review for gene: TSEN54 was set to GREEN
gene: TSEN54 was marked as current diagnostic
Added comment: Microcephaly is a common feature of TSEN54 pontocerebellar hypoplasia (progressive in type 2, present at birth in type 4).
Sources: Expert list
Severe microcephaly v2.20 TSEN15 Zornitza Stark gene: TSEN15 was added
gene: TSEN15 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TSEN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN15 were set to 27392077
Phenotypes for gene: TSEN15 were set to Pontocerebellar hypoplasia, type 2F MIM#617026
Review for gene: TSEN15 was set to GREEN
gene: TSEN15 was marked as current diagnostic
Added comment: PMID 27392077 Reports four individuals from three families with PCH type 2 and different homozygous missense variants, all had progressive microcephaly (between -3SD and -9.7SD). Functional studies indicated that all variants resulted in almost complete lack of in vitro tRNA cleavage activity.
Sources: Expert list
Severe microcephaly v2.20 TRIO Zornitza Stark gene: TRIO was added
gene: TRIO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRIO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIO were set to 26721934; 32109419
Phenotypes for gene: TRIO were set to Mental retardation, autosomal dominant 44, MIM# 617061
Review for gene: TRIO was set to GREEN
gene: TRIO was marked as current diagnostic
Added comment: The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly.
Sources: Expert list
Severe microcephaly v2.20 DYNC1I2 Zornitza Stark gene: DYNC1I2 was added
gene: DYNC1I2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492
Review for gene: DYNC1I2 was set to GREEN
gene: DYNC1I2 was marked as current diagnostic
Added comment: Five individuals from three unrelated families reported.
Sources: Expert list
Severe microcephaly v2.20 DPM1 Zornitza Stark gene: DPM1 was added
gene: DPM1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DPM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPM1 were set to 16641202; 10642602; 10642597
Phenotypes for gene: DPM1 were set to Congenital disorder of glycosylation, type Ie 608799
Review for gene: DPM1 was set to GREEN
gene: DPM1 was marked as current diagnostic
Added comment: PMID: 16641202 - 2 siblings of consanguineous parents. One patient showed retarded motor skills at 1, 2 and 4 years old, with distal myopathy present at 3 years of age. The younger sister presented at 7 weeks of age with generalized hypotonia. Both had normal CK levels. Both siblings were progressively microcephalic.

PMID: 10642602 - 2 chet siblings with hypotonia within the first year of life. Both had elevated CK. Both siblings were progressively microcephalic

PMID: 10642597 - 2 unrelated patients. One had profound hypotonia at 3 years of age. The other patient was markedly hypotonic in infancy. Both were microcephalic and hd elevated CK levels.
Sources: Expert list
Severe microcephaly v2.20 DNMT3A Zornitza Stark gene: DNMT3A was added
gene: DNMT3A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DNMT3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNMT3A were set to 30478443
Phenotypes for gene: DNMT3A were set to intellectual disability; microcephaly; short stature
Review for gene: DNMT3A was set to GREEN
gene: DNMT3A was marked as current diagnostic
Added comment: Three individuals reported, two with the same de novo missense variant. Postulated to be GOF as opposed to LOF variants in this gene which cause an overgrowth syndrome. Animal model supports pathogenicity.
Sources: Expert list
Severe microcephaly v2.20 DNA2 Zornitza Stark reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, MIM#615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.20 CTU2 Zornitza Stark gene: CTU2 was added
gene: CTU2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MIM#618142)
Review for gene: CTU2 was set to GREEN
gene: CTU2 was marked as current diagnostic
Added comment: Dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL) as proposed by authors.

PMID: 26633546
- 3 consanguineous families all with the same splice variant (NM_001012762.1:c.873G>A). Assumed to be founder variant
- all had microcephaly but measurements were not provided

PMID: 27480277
- 2 additional patients from an extended consanguineous family with the same variant as above
- Patient 1: head circumference of -3.5SD at birth, not growing
- Patient 2: head circumference of -4.3 SD

PMID: 31301155
- 5 new patients with microcephaly (no measurements provided)
- 3x PTVs and 1x missense
Sources: Expert list
Severe microcephaly v2.20 CTSF Zornitza Stark gene: CTSF was added
gene: CTSF was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CTSF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTSF were set to 23746550; 30893510; 28619046
Phenotypes for gene: CTSF were set to Mental retardation, autosomal dominant 21 (MIM#615502)
Review for gene: CTSF was set to GREEN
gene: CTSF was marked as current diagnostic
Added comment: PMID: 23746550
- 4 probands, 2x PTV, 1x missense, 1x 280kb deletion (all de novo)
- OFCs ranges from -0.8 SD (the proband with the deletion) to -3.51 SD

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

PMID: 28619046
- 1x proband with de novo fs
- head circumference was under 10th centle
Sources: Expert list
Severe microcephaly v2.20 CSNK2A1 Zornitza Stark gene: CSNK2A1 was added
gene: CSNK2A1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CSNK2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK2A1 were set to 29240241
Phenotypes for gene: CSNK2A1 were set to Okur-Chung neurodevelopmental syndrome MIM#617062
Review for gene: CSNK2A1 was set to GREEN
gene: CSNK2A1 was marked as current diagnostic
Added comment: Microcephaly is a feature of the condition in 8/14 cases with de novo variants.
Sources: Expert list
Severe microcephaly v2.20 CHAMP1 Zornitza Stark gene: CHAMP1 was added
gene: CHAMP1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CHAMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHAMP1 were set to 27148580; 26340335
Phenotypes for gene: CHAMP1 were set to Mental retardation, autosomal dominant 40 (MIM#616579)
Review for gene: CHAMP1 was set to GREEN
gene: CHAMP1 was marked as current diagnostic
Added comment: PMID: 27148580;
- 10 patients including 5 from Hempel et al (PMID: 26340335)
- 7 with microcephaly defined as <3rd centile
- all PTVs and de novo

PMID: 26340335;
- 5 unrelated patients OFC at birth ranges from -0.4 to -3.1 SD
Sources: Expert list
Severe microcephaly v2.20 CEP63 Zornitza Stark reviewed gene: CEP63: Rating: AMBER; Mode of pathogenicity: None; Publications: 21983783, 26158450; Phenotypes: Seckel syndrome 6, MIM#614728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 BUB1B Zornitza Stark gene: BUB1B was added
gene: BUB1B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1B were set to 18548531
Phenotypes for gene: BUB1B were set to Mosaic variegated aneuploidy syndrome 1 (MIM#257300)
Review for gene: BUB1B was set to GREEN
gene: BUB1B was marked as current diagnostic
Added comment: Severe microcephaly is a feature of MVAS. PMID: 18548531: review of 13 families with 12 presenting with microcephaly
Sources: Expert list
Severe microcephaly v2.20 BPTF Zornitza Stark gene: BPTF was added
gene: BPTF was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BPTF were set to 28942966
Phenotypes for gene: BPTF were set to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755
Review for gene: BPTF was set to GREEN
gene: BPTF was marked as current diagnostic
Added comment: Microcephaly observed in 7/9 individuals reported.
Sources: Expert list
Severe microcephaly v2.20 AARS Zornitza Stark gene: AARS was added
gene: AARS was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 28493438; 25817015
Phenotypes for gene: AARS were set to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Review for gene: AARS was set to GREEN
gene: AARS was marked as current diagnostic
Added comment: Bi-allelic variants associated with a severe phenotype comprising leukodystrophy, epilepsy, microcephaly and neurodevelopmental delay reported in three families.
Sources: Expert list
Severe microcephaly v2.20 FOXG1 Zornitza Stark gene: FOXG1 was added
gene: FOXG1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: FOXG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037
Phenotypes for gene: FOXG1 were set to Rett syndrome, congenital variant, MIM# 613454
Review for gene: FOXG1 was set to GREEN
gene: FOXG1 was marked as current diagnostic
Added comment: More than 20 individuals reported with de novo variants in this gene. Microcephaly is part of the phenotype.
Sources: Expert list
Severe microcephaly v2.20 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Expert list
Severe microcephaly v2.20 EIF2S3 Zornitza Stark gene: EIF2S3 was added
gene: EIF2S3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EIF2S3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: EIF2S3 were set to 23063529; 27333055; 28055140; 32799315
Phenotypes for gene: EIF2S3 were set to MEHMO syndrome, MIM# 300148
Review for gene: EIF2S3 was set to GREEN
Added comment: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity).
Sources: Expert list
Early onset or syndromic epilepsy v2.148 TRIP13 Zornitza Stark changed review comment from: Phenotype is highly variable but seizures reported in 2/6 cases.; to: Phenotype is highly variable but seizures reported in 2/6 cases. Note 5/6 families had the same homozygous variant, p.Arg354X, suggestive of founder effect.
Early onset or syndromic epilepsy v2.148 TRIP13 Zornitza Stark edited their review of gene: TRIP13: Changed rating: AMBER
Severe microcephaly v2.20 TRAPPC9 Zornitza Stark gene: TRAPPC9 was added
gene: TRAPPC9 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC9 were set to 22549410; 20004765; 20004763; 30853973
Phenotypes for gene: TRAPPC9 were set to Mental retardation, autosomal recessive 13, MIM# 613192
Review for gene: TRAPPC9 was set to GREEN
gene: TRAPPC9 was marked as current diagnostic
Added comment: Microcephaly is part of the phenotype.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC6B Zornitza Stark gene: TRAPPC6B was added
gene: TRAPPC6B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC6B were set to 28626029; 28397838; 31687267
Phenotypes for gene: TRAPPC6B were set to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Review for gene: TRAPPC6B was set to GREEN
gene: TRAPPC6B was marked as current diagnostic
Added comment: Five unrelated families reported with autosomal recessive neurodegenerative disorder characterised by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC12 Zornitza Stark gene: TRAPPC12 was added
gene: TRAPPC12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC12 were set to 32369837; 28777934
Phenotypes for gene: TRAPPC12 were set to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Review for gene: TRAPPC12 was set to GREEN
gene: TRAPPC12 was marked as current diagnostic
Added comment: Four families reported with a severe progressive encephalopathy characterized by microcephaly, global developmental delay, and hearing loss.
Sources: Expert list
Severe microcephaly v2.20 TPRKB Zornitza Stark gene: TPRKB was added
gene: TPRKB was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TPRKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPRKB were set to 28805828; 30053862
Phenotypes for gene: TPRKB were set to Galloway-Mowat syndrome 5, MIM# 617731
Review for gene: TPRKB was set to GREEN
gene: TPRKB was marked as current diagnostic
Added comment: Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly.
Sources: Expert list
Severe microcephaly v2.20 TP53RK Zornitza Stark gene: TP53RK was added
gene: TP53RK was added to Severe microcephaly. Sources: Expert Review
Mode of inheritance for gene: TP53RK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP53RK were set to 28805828; 30053862
Phenotypes for gene: TP53RK were set to Galloway-Mowat syndrome 4, MIM# 617730
Review for gene: TP53RK was set to GREEN
gene: TP53RK was marked as current diagnostic
Added comment: At least 4 unrelated families reported with renal-neurologic disease characterised by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities, and delayed psychomotor development. Most individuals have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable.
Sources: Expert Review
Severe microcephaly v2.20 TCF4 Zornitza Stark gene: TCF4 was added
gene: TCF4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TCF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF4 were set to 18728071; 22934316
Phenotypes for gene: TCF4 were set to Pitt-Hopkins syndrome, MIM# 610954
Review for gene: TCF4 was set to GREEN
gene: TCF4 was marked as current diagnostic
Added comment: Well established gene-disease association. Microcephaly reported in around 60%.
Sources: Expert list
Intellectual disability v3.284 CCDC88A Arina Puzriakova Classified gene: CCDC88A as Amber List (moderate evidence)
Intellectual disability v3.284 CCDC88A Arina Puzriakova Added comment: Comment on list classification: This gene has been upgraded from Red to Amber based on the external reviews by Konstantinos Varvagiannis and Zornitza Stark.
Intellectual disability v3.284 CCDC88A Arina Puzriakova Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.283 CCDC174 Arina Puzriakova Classified gene: CCDC174 as Red List (low evidence)
Intellectual disability v3.283 CCDC174 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only one founder variant reported to-date in a single publication - currently no evidence that other variants in this gene are disease-causing.

Added 'founder-effect' tag
Intellectual disability v3.283 CCDC174 Arina Puzriakova Gene: ccdc174 has been classified as Red List (Low Evidence).
Intellectual disability v3.282 CCDC174 Arina Puzriakova Tag founder-effect tag was added to gene: CCDC174.
Intellectual disability v3.282 TAF1C Arina Puzriakova Classified gene: TAF1C as Amber List (moderate evidence)
Intellectual disability v3.282 TAF1C Arina Puzriakova Gene: taf1c has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 TET2 Boaz Palterer gene: TET2 was added
gene: TET2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TET2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TET2 were set to 32518946
Phenotypes for gene: TET2 were set to Primary Immunodeficiency; Lymphoma; Hepatosplenomegaly; Autoimmunity; Developmental delay
Penetrance for gene: TET2 were set to unknown
Review for gene: TET2 was set to AMBER
Added comment: Sources: Literature
Congenital myopathy v2.5 CFL2 Arina Puzriakova reviewed gene: CFL2: Rating: ; Mode of pathogenicity: None; Publications: 32160286; Phenotypes: Nemaline myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.13 TDRD7 Arina Puzriakova reviewed gene: TDRD7: Rating: ; Mode of pathogenicity: None; Publications: 32420594; Phenotypes: Congenital cataracts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.281 PAK3 Arina Puzriakova reviewed gene: PAK3: Rating: ; Mode of pathogenicity: None; Publications: 31943058; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Severe microcephaly v2.20 SVBP Zornitza Stark gene: SVBP was added
gene: SVBP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SVBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVBP were set to 31363758; 30607023
Phenotypes for gene: SVBP were set to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569
Review for gene: SVBP was set to GREEN
Added comment: 5 unrelated families with homozygous mutations in SVBP, microcephaly is part of the phenotype. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Expert list
Severe microcephaly v2.20 SMO Zornitza Stark gene: SMO was added
gene: SMO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMO were set to 32413283
Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis
Review for gene: SMO was set to GREEN
gene: SMO was marked as current diagnostic
Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Sources: Expert list
Severe microcephaly v2.20 SLC1A4 Zornitza Stark gene: SLC1A4 was added
gene: SLC1A4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SLC1A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A4 were set to 25930971; 26138499; 26041762; 27193218; 29989513
Phenotypes for gene: SLC1A4 were set to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657
Review for gene: SLC1A4 was set to GREEN
Added comment: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures. Multiple affected families reported. Note founder variant p.Glu256Lys is a common founder variant in the Ashkenazi Jewish population.
Sources: Expert list
Severe microcephaly v2.20 SASS6 Zornitza Stark reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 24951542, 30639237; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 RUSC2 Zornitza Stark gene: RUSC2 was added
gene: RUSC2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: RUSC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RUSC2 were set to 27612186
Phenotypes for gene: RUSC2 were set to Mental retardation, autosomal recessive 61, MIM# 617773
Review for gene: RUSC2 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert list
Severe microcephaly v2.20 PUS7 Zornitza Stark gene: PUS7 was added
gene: PUS7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PUS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS7 were set to 30526862; 30778726; 31583274
Phenotypes for gene: PUS7 were set to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM #618342
Review for gene: PUS7 was set to GREEN
gene: PUS7 was marked as current diagnostic
Added comment: 11 patients from 6 families with ID, speech delay, short stature, microcephaly, and aggressive behavior, with homozygous PUS7 mutations, which segregated with disease.
Sources: Expert list
Severe microcephaly v2.20 PUF60 Zornitza Stark gene: PUF60 was added
gene: PUF60 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUF60 were set to 28327570
Phenotypes for gene: PUF60 were set to Verheij syndrome, MIM# 615583
Review for gene: PUF60 was set to GREEN
gene: PUF60 was marked as current diagnostic
Added comment: Over 15 affected individuals reported. Short stature and dev delay are consistent features. 5/12 in the largest case series had microcephaly in relation to stature (Z-scores −2.48, −4.22, −2.09, −2.99, −2.53 respectively).
Sources: Expert list
Severe microcephaly v2.20 PTPN23 Zornitza Stark gene: PTPN23 was added
gene: PTPN23 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PTPN23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN23 were set to 31395947; 29899372; 29090338; 27848944; 25558065
Phenotypes for gene: PTPN23 were set to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890
Review for gene: PTPN23 was set to GREEN
Added comment: Over 10 families reported with an autosomal recessive neurologic disorder characterised by global developmental delay apparent from early infancy, poor overall growth often with microcephaly (6/10), impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum.
Sources: Expert list
Severe microcephaly v2.20 PPP1R15B Zornitza Stark reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27640355; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 POGZ Zornitza Stark gene: POGZ was added
gene: POGZ was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: POGZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POGZ were set to 26942287
Phenotypes for gene: POGZ were set to White-Sutton syndrome, MIM# 616364
Review for gene: POGZ was set to GREEN
gene: POGZ was marked as current diagnostic
Added comment: Microcephaly is reported in around half of affected individuals.
Sources: Expert list
Severe microcephaly v2.20 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to Primary microcephaly
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. Borderline Red/Amber rating in view of the supportive animal model data.
Sources: Expert list
Severe microcephaly v2.20 DPP6 Zornitza Stark reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23832105; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 MCM10 Boaz Palterer edited their review of gene: MCM10: Changed phenotypes: NK Cell deficiency, primary Immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 TNFSF13 Boaz Palterer gene: TNFSF13 was added
gene: TNFSF13 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF13 were set to 32298700
Phenotypes for gene: TNFSF13 were set to APRIL deficiency; Common variable immunodeficiency
Penetrance for gene: TNFSF13 were set to unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 TOM1 Boaz Palterer gene: TOM1 was added
gene: TOM1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TOM1 were set to 31263572
Phenotypes for gene: TOM1 were set to early-onset autoimmunity; antibody deficiency; combined immunodeficiency; primary immunodeficiency
Penetrance for gene: TOM1 were set to unknown
Review for gene: TOM1 was set to RED
Added comment: Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 MAPK8 Boaz Palterer gene: MAPK8 was added
gene: MAPK8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MAPK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK8 were set to 31901076
Phenotypes for gene: MAPK8 were set to chronic mucocutaneous candidiasis; connective tissue disorders
Penetrance for gene: MAPK8 were set to unknown
Review for gene: MAPK8 was set to AMBER
Added comment: Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 CTNNBL1 Boaz Palterer gene: CTNNBL1 was added
gene: CTNNBL1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CTNNBL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNBL1 were set to 32484799
Phenotypes for gene: CTNNBL1 were set to Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency
Penetrance for gene: CTNNBL1 were set to unknown
Review for gene: CTNNBL1 was set to AMBER
Added comment: Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 MCM10 Boaz Palterer gene: MCM10 was added
gene: MCM10 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM10 were set to 32865517
Penetrance for gene: MCM10 were set to unknown
Review for gene: MCM10 was set to AMBER
Added comment: Compound heterozygous variants in minichromosomal maintenance complex member 10 (MCM10) were reported as a cause of NK-cell deficiency in a child with fatal susceptibility to CMV.
Sources: Literature
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Classified gene: TRAPPC2L as Amber List (moderate evidence)
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional cases required to delineate the genotype-phenotype relationship. Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications.
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.280 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.49 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, adult onset v1.5 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Possible mitochondrial disorder, nuclear genes v1.16 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Monogenic hearing loss v2.45 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.278 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.147 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Fetal anomalies v1.95 TOGARAM1 Arina Puzriakova Classified gene: TOGARAM1 as Red List (low evidence)
Fetal anomalies v1.95 TOGARAM1 Arina Puzriakova Added comment: Comment on list classification: Single family. Additional cases required to corroborate pathogenicity.
Fetal anomalies v1.95 TOGARAM1 Arina Puzriakova Gene: togaram1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.94 TOGARAM1 Arina Puzriakova gene: TOGARAM1 was added
gene: TOGARAM1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439
Phenotypes for gene: TOGARAM1 were set to Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus
Added comment: PMID: 32747439 (2020) - Novel gene-disease association. In two sibling fetuses with a malformation disorder characterised by microcephaly, severe cleft lip and palate, microphthalmia, and brain anomalies, WES revealed compound heterozygous variants ([c.1102C>T, p.Arg368Trp] and [c.3619C>T, p.Arg1207*]) in the TOGARAM1 gene.

Functional analysis of the missense variant in a C. elegans model showed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. In vitro analysis revealed faster microtubule polymerisation compared to wild-type, suggesting aberrant tubulin binding.
Sources: Literature
Severe microcephaly v2.20 PCDH12 Zornitza Stark gene: PCDH12 was added
gene: PCDH12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDH12 were set to 27164683; 22822038; 30178464
Phenotypes for gene: PCDH12 were set to Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280
Review for gene: PCDH12 was set to GREEN
Added comment: Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present. At least 12 families reported.
Sources: Expert list
Cerebral vascular malformations v2.5 CCM2 Arina Puzriakova Publications for gene: CCM2 were set to 20301470; 14624391
Intellectual disability v3.278 SUPT16H Arina Puzriakova Publications for gene: SUPT16H were set to http://dx.doi.org/10.1136/jmedgenet-2019-106193
Intellectual disability v3.277 SUPT16H Arina Puzriakova Classified gene: SUPT16H as Amber List (moderate evidence)
Intellectual disability v3.277 SUPT16H Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated GREEN at the next major review - at least four unrelated individuals with GDD/ID (plus another additional patient with a deletion, albeit encompassing other potentially clinically relevant genes).
Intellectual disability v3.277 SUPT16H Arina Puzriakova Gene: supt16h has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.276 SUPT16H Arina Puzriakova Tag for-review tag was added to gene: SUPT16H.
Severe microcephaly v2.20 ERCC5 Zornitza Stark edited their review of gene: ERCC5: Changed publications: 32052936, 24700531
Severe microcephaly v2.20 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 32052936; Phenotypes: Cerebrooculofacioskeletal syndrome 3 MIM#616570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 COASY Sebastian Lunke reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 28489334; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v2.3 CTNND1 Eleanor Williams changed review comment from: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).; to: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).
Clefting v2.3 CTNND1 Eleanor Williams reviewed gene: CTNND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32196547; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.9 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to
Hereditary ataxia, adult onset v2.8 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.45 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to PMID:10325416; 10433969; 10449766; 10545955; 10615135; 10721735; 10753866; 10801130; 10888872; 10888886; 11005794; 11074872; 11290321; 11728338; 11884600; 11932749; 11940649; 12145218; 12473678; 12496760; 12702876; 12915469; 14615517; 14684836; 14749379; 14978102; 15215866; 15311210; 1559980; 15657147; 15684088; 15870198; 1594447; 1606615; 16357870; 16998846; 17312023; 17322882; 17359920; 17470536; 17673620; 17960246; 17994007; 18194272; 19098913; 19246518; 19433415; 1968655; 20081831; 2014266; 21163962; 21532572; 22323818; 22328086; 23365052; 24013172; 24107992; 3210246; 7898717; 8747854; 8917520; 8940105; 9302295; 9333948; 9449671
Monogenic hearing loss v2.44 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy v1.376 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 21532572
Hereditary neuropathy v1.375 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Paroxysmal central nervous system disorders v1.4 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 23904686; 22328086; 24709307
Paroxysmal central nervous system disorders v1.3 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.205 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.7 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to
Ataxia and cerebellar anomalies - childhood onset v2.6 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.48 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Kleine-Levin syndrome v1.5 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 22328086; 24709307; 23904686
Kleine-Levin syndrome v1.4 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Neurodegenerative disorders, adult onset v2.16 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 23365052; 8747854; 22328086
Neurodegenerative disorders, adult onset v2.15 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.44 RIPOR2 Arina Puzriakova Added comment: Comment on mode of inheritance: Only two publications, describing different patterns of inheritance (AR or AD).
Monogenic hearing loss v2.44 RIPOR2 Arina Puzriakova Mode of inheritance for gene: RIPOR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.43 RIPOR2 Arina Puzriakova Classified gene: RIPOR2 as Amber List (moderate evidence)
Monogenic hearing loss v2.43 RIPOR2 Arina Puzriakova Added comment: Comment on list classification: Recent publication described several families, but with a founder variant. Therefore currently still insufficient cases for a rating upgrade.
Monogenic hearing loss v2.43 RIPOR2 Arina Puzriakova Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.42 RIPOR2 Arina Puzriakova reviewed gene: RIPOR2: Rating: ; Mode of pathogenicity: None; Publications: 32631815; Phenotypes: Sensorineural hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v2.15 NOTCH3 Eleanor Williams Publications for gene: NOTCH3 were set to
Neurodegenerative disorders, adult onset v2.14 NOTCH3 Eleanor Williams reviewed gene: NOTCH3: Rating: ; Mode of pathogenicity: None; Publications: 31960911; Phenotypes: ; Mode of inheritance: None
Neurodegenerative disorders, adult onset v2.14 TET2 Eleanor Williams gene: TET2 was added
gene: TET2 was added to Neurodegenerative disorders - adult onset. Sources: Literature
Mode of inheritance for gene: TET2 was set to Unknown
Publications for gene: TET2 were set to 31943063
Added comment: PMID: 31943063 - Li et al 2020 - functional studies in mice show that Tet2 depletion in the hippocampus exacerbates Alzheimer disease pathology and cognitive dysfunction at early disease stages
Sources: Literature
Cholestasis v1.24 ZFYVE19 Arina Puzriakova Tag for-review tag was added to gene: ZFYVE19.
Cholestasis v1.24 ZFYVE19 Arina Puzriakova Classified gene: ZFYVE19 as Amber List (moderate evidence)
Cholestasis v1.24 ZFYVE19 Arina Puzriakova Gene: zfyve19 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.23 ZFYVE19 Arina Puzriakova gene: ZFYVE19 was added
gene: ZFYVE19 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: ZFYVE19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE19 were set to 32737136
Phenotypes for gene: ZFYVE19 were set to Cholestasis
Review for gene: ZFYVE19 was set to GREEN
Added comment: PMID: 32737136 (2020) - Nine Han Chinese children from seven families with biallelic, predicted complete LoF variants in ZFYVE19. All patients had high-GGT intrahepatic cholestasis, portal hypertension, and histopathological features of the ductal plate malformation/congenital hepatic fibrosis.

ZFYVE19 depletion in cultured cells from one patient yielded centriolar and axonemal abnormalities, and immunostaining for two ciliary proteins DCDC2 and ACALT showed abnormal localisation in patient cholangiocytes, indicating this as a novel ciliopathy disorder.
Sources: Literature
Hereditary neuropathy v1.375 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to 25428574
Hereditary neuropathy v1.374 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Paediatric motor neuronopathies v1.33 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to 25428574
Paediatric motor neuronopathies v1.32 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Possible mitochondrial disorder, nuclear genes v1.16 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Possible mitochondrial disorder, nuclear genes v1.15 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.419 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Neurodegenerative disorders, adult onset v2.13 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to 25113787; 30014597; 27810918; 25576308; 24934289
Likely inborn error of metabolism v2.18 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Likely inborn error of metabolism v2.17 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.418 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Neurodegenerative disorders, adult onset v2.12 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.20 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Early onset or syndromic epilepsy v2.147 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Intellectual disability v3.276 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Intellectual disability v3.275 ADARB1 Arina Puzriakova Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Severe microcephaly v2.19 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Early onset or syndromic epilepsy v2.146 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Intellectual disability v3.274 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
VACTERL-like phenotypes v1.27 KIAA1217 Eleanor Williams Classified gene: KIAA1217 as Amber List (moderate evidence)
VACTERL-like phenotypes v1.27 KIAA1217 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team rating this gene amber. Although there are 10 cases reported, the mode of inheritance and level of penterance is not clear, and it would be useful to have more information prior to diagnostic use
VACTERL-like phenotypes v1.27 KIAA1217 Eleanor Williams Gene: kiaa1217 has been classified as Amber List (Moderate Evidence).
VACTERL-like phenotypes v1.26 KIAA1217 Eleanor Williams gene: KIAA1217 was added
gene: KIAA1217 was added to VACTERL-like phenotypes. Sources: Literature
Mode of inheritance for gene: KIAA1217 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KIAA1217 were set to 32369272
Phenotypes for gene: KIAA1217 were set to vertebral malformations
Review for gene: KIAA1217 was set to AMBER
Added comment: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations. 1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency. In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Not associated with any phenotype in OMIM or Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams changed review comment from: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations.  1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency.  In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available.
Sources: Literature; to: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations.  1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency.  In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Not associated with any phenotype in OMIM or Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Classified gene: KIAA1217 as Amber List (moderate evidence)
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team rating this gene amber. Although there are 10 cases reported, the mode of inheritance and level of penterance is not clear, and it would be useful to have more information prior to diagnostic use
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Gene: kiaa1217 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.14 KIAA1217 Eleanor Williams Tag for-review tag was added to gene: KIAA1217.
Skeletal dysplasia v2.14 KIAA1217 Eleanor Williams gene: KIAA1217 was added
gene: KIAA1217 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: KIAA1217 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KIAA1217 were set to 32369272
Phenotypes for gene: KIAA1217 were set to vertebral malformations
Review for gene: KIAA1217 was set to AMBER
Added comment: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations.  1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency.  In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available.
Sources: Literature
Severe microcephaly v2.19 HIST1H4C Zornitza Stark gene: HIST1H4C was added
gene: HIST1H4C was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: HIST1H4C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4C were set to 28920961
Phenotypes for gene: HIST1H4C were set to Growth delay, microcephaly and intellectual disability
Review for gene: HIST1H4C was set to GREEN
gene: HIST1H4C was marked as current diagnostic
Added comment: Two families and a zebrafish model reported initially, another case identified through clinical testing internally.
Sources: Expert list
Severe microcephaly v2.19 KIF14 Zornitza Stark gene: KIF14 was added
gene: KIF14 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to 28892560; 29343805
Phenotypes for gene: KIF14 were set to Microcephaly 20, primary, autosomal recessive, MIM# 617914
Review for gene: KIF14 was set to GREEN
gene: KIF14 was marked as current diagnostic
Added comment: At least 8 families reported. Microcephaly ranged from -3.6 to -11 SD.
Sources: Expert list
Severe microcephaly v2.19 LAGE3 Zornitza Stark edited their review of gene: LAGE3: Set current diagnostic: yes
Severe microcephaly v2.19 LAGE3 Zornitza Stark gene: LAGE3 was added
gene: LAGE3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: LAGE3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: LAGE3 were set to 28805828
Phenotypes for gene: LAGE3 were set to Galloway-Mowat syndrome 2, X-linked, MIM# 301006
Review for gene: LAGE3 was set to GREEN
Added comment: Renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. At least three unrelated families and a mouse model.
Sources: Expert list
Severe microcephaly v2.19 OSGEP Zornitza Stark gene: OSGEP was added
gene: OSGEP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: OSGEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSGEP were set to 28805828; 28272532
Phenotypes for gene: OSGEP were set to Galloway-Mowat syndrome 3, MIM# 617729
Review for gene: OSGEP was set to GREEN
gene: OSGEP was marked as current diagnostic
Added comment: Early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most individuals have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Over 25 families reported.
Sources: Expert list
Severe microcephaly v2.19 NUP188 Zornitza Stark gene: NUP188 was added
gene: NUP188 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 28726809; 32275884
Phenotypes for gene: NUP188 were set to microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Review for gene: NUP188 was set to GREEN
gene: NUP188 was marked as current diagnostic
Added comment: Eight unrelated individuals reported.
Sources: Expert list
Severe microcephaly v2.19 NUP107 Zornitza Stark gene: NUP107 was added
gene: NUP107 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NUP107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP107 were set to 28280135; 28117080; 30179222; 25558065
Phenotypes for gene: NUP107 were set to Galloway-Mowat syndrome 7, MIM# 618348
Review for gene: NUP107 was set to GREEN
gene: NUP107 was marked as current diagnostic
Added comment: Autosomal recessive disorder characterised by developmental delay, microcephaly (-5 to -9 SD), and early-onset nephrotic syndrome. Approx 10 families reported. Recurrent variant p.Met101Ile identified in several families, likely represents a South Asian founder allele.
Sources: Expert list
Severe microcephaly v2.19 VRK1 Zornitza Stark gene: VRK1 was added
gene: VRK1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VRK1 were set to 19646678; 24126608; 27281532; 31560180
Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A MIM#607596
Review for gene: VRK1 was set to GREEN
gene: VRK1 was marked as current diagnostic
Added comment: PMID 19646678: A homozygous nonsense variant was identified in an affected Ashkenazi Jewish family with 3 individuals with SMA-PCH. 2 had severe microcephaly (-6SD at 5yo and -7.9SD at 19mo). The third was noted to be microcephalic but no figures given. PMID 24126608: "Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly". 2 sibs from one family had head circumference -4SD and -6SD and were chet for missense variants. The third unrelated individual was -6SD and hom for a nonsense variant. PMID 27281532: reports another individual with microcephaly but no details provided.
Sources: Expert list
Severe microcephaly v2.19 BRD4 Zornitza Stark gene: BRD4 was added
gene: BRD4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BRD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRD4 were set to 29379197; 30302754
Phenotypes for gene: BRD4 were set to Cornelia de Lange-like syndrome
Review for gene: BRD4 was set to AMBER
Added comment: A mixture of evidence from SNVs and CNVs. Note the CNVs are large and only some individuals have documented OFC < -3SD.

PMID: 29379197;
- 4x patients reports however only 3 reported with occipitofrontal circumference of < -3 SD
- 1x microdeletion of 1.04Mb, 1x missense and 1x fs. All de novo

PMID: 30302754
- 1x proband with occipitofrontal circumference 28 cm (−2 SD)
- de novo interstitial deletion involving the short arm of a chromosome 19, 1.97 Mb in size, which included BRD4
Sources: Expert list
Severe microcephaly v2.19 WDR4 Zornitza Stark reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26416026, 28617965, 30079490, 29597095; Phenotypes: Galloway-Mowat syndrome 6 MIM#618347; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 WDR37 Zornitza Stark edited their review of gene: WDR37: Set current diagnostic: yes
Severe microcephaly v2.19 WDR37 Zornitza Stark gene: WDR37 was added
gene: WDR37 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR37 were set to 31327508; 31327510
Phenotypes for gene: WDR37 were set to Neurooculocardiogenitourinary syndrome MIM#618652
Review for gene: WDR37 was set to GREEN
Added comment: Summary: 7/9 individuals reported with neurooculocardiogenitourinary syndrome had microcephaly. 5 had measurements provided and were severe (-3SD).

PMID 31327510: 4 individuals with de novo missense variants reported, with Neurooculocardiogenitourinary syndrome. All four have microcephaly - 49.5cm at 21yo, 40.2cm at 22mo (-4.8SD), 47.4cm at 7.5yo.

PMID 31327508: 5 probands with de novo missense variants, 3 with microcephaly (0th centile, <3rd centile (-5SD), and 11th centile)
Sources: Expert list
Severe microcephaly v2.19 ATP1A2 Zornitza Stark gene: ATP1A2 was added
gene: ATP1A2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 30690204; 31608932
Phenotypes for gene: ATP1A2 were set to hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations
Review for gene: ATP1A2 was set to GREEN
gene: ATP1A2 was marked as current diagnostic
Added comment: This is a distinct phenotype from the one associated with mono-allelic variants.

PMID: 30690204;
- 2 families with severe microcephaly (-6 to -8 SD)
- both homozygous PTVs

PMID: 31608932;
- 4 patients from 2 families
- Family A, all 3 affecteds had severe microcephaly during ultrasound (-3 to -4 SD)
- Family B, no measurements were reported
- both homozygous PTVs
Sources: Expert list
Severe microcephaly v2.19 ARCN1 Zornitza Stark gene: ARCN1 was added
gene: ARCN1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARCN1 were set to 27476655
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164)
Review for gene: ARCN1 was set to GREEN
gene: ARCN1 was marked as current diagnostic
Added comment: Borderline Amber/Green. Microcephaly is a key part of the phenotype but few exact measurements actually reported.
Sources: Expert list
Severe microcephaly v2.19 AP4S1 Zornitza Stark gene: AP4S1 was added
gene: AP4S1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4S1 were set to 21620353; 25552650; 27444738
Phenotypes for gene: AP4S1 were set to Spastic paraplegia 52, autosomal recessive (MIM#614067)
Review for gene: AP4S1 was set to GREEN
gene: AP4S1 was marked as current diagnostic
Added comment: Borderline Amber/Green as only one affected individual <-3SD; however, part of same gene family as other spastic paraplegias with microcephaly. Microcephaly in another family -2SD and precise information on the microcephaly not available for third family.
Sources: Expert list
Severe microcephaly v2.19 AP4M1 Zornitza Stark gene: AP4M1 was added
gene: AP4M1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4M1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4M1 were set to 28464862; 24700674
Phenotypes for gene: AP4M1 were set to Spastic paraplegia 50, autosomal recessive (MIM#612936)
Review for gene: AP4M1 was set to GREEN
gene: AP4M1 was marked as current diagnostic
Added comment: Despite the OMIM name, this is a complex neurological condition, where microcephaly is an early prominent presenting feature.

PMID: 28464862;
- 1x with severe progressive microcephaly (< - 4 SD)
- homozygous nonsense

PMID: 24700674;
- 2x unrelated patients (1 and 3) < -3 SD head circumference
- 2x homozygous nonsense
Sources: Expert list
Severe microcephaly v2.19 NSD2 Zornitza Stark gene: NSD2 was added
gene: NSD2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSD2 were set to 30345613; 31171569
Phenotypes for gene: NSD2 were set to microcephaly; intellectual disability
Review for gene: NSD2 was set to GREEN
Added comment: Microcephaly reported in 6 of 7 individuals with LOF variants in this gene.
Sources: Expert list
Severe microcephaly v2.19 ZNF335 Zornitza Stark reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087; Phenotypes: Microcephaly 10, primary, autosomal recessive (MIM#615095); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 MED17 Zornitza Stark gene: MED17 was added
gene: MED17 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MED17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Phenotypes for gene: MED17 were set to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668
Review for gene: MED17 was set to GREEN
gene: MED17 was marked as current diagnostic
Added comment: Five individuals from four families reported initially, founder effect for p.Leu371Pro. Two additional families reported since with different variants, one family with milder phenotype.
Sources: Expert list
Severe microcephaly v2.19 MECP2 Zornitza Stark gene: MECP2 was added
gene: MECP2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MECP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: MECP2 were set to Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673
Review for gene: MECP2 was set to GREEN
gene: MECP2 was marked as current diagnostic
Added comment: Well established gene-disease association, microcephaly is a key phenotypic feature both in Rett syndrome and in males affected by severe neonatal encephalopathy.
Sources: Expert list
Severe microcephaly v2.19 AKT3 Zornitza Stark changed review comment from: Activating variants in AKT2 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list; to: Activating variants in AKT3 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list
Severe microcephaly v2.19 AKT3 Zornitza Stark gene: AKT3 was added
gene: AKT3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AKT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AKT3 were set to 32827175; 31929334; 30853971; 30053339; 25424989
Phenotypes for gene: AKT3 were set to Microcephaly
Review for gene: AKT3 was set to AMBER
Added comment: Activating variants in AKT2 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list
Severe microcephaly v2.19 AP4E1 Zornitza Stark gene: AP4E1 was added
gene: AP4E1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4E1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4E1 were set to 20972249; 21620353; 21937992
Phenotypes for gene: AP4E1 were set to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Review for gene: AP4E1 was set to GREEN
gene: AP4E1 was marked as current diagnostic
Added comment: Autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development. Microcephaly is a prominent, presenting feature. At least 3 families reported.
Sources: Expert list
Severe microcephaly v2.19 AP4B1 Zornitza Stark gene: AP4B1 was added
gene: AP4B1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Review for gene: AP4B1 was set to GREEN
gene: AP4B1 was marked as current diagnostic
Added comment: Microcephaly is an early, prominent presenting feature of this progressive neurological disorder. At least 4 unrelated families reported.
Sources: Expert list
Severe microcephaly v2.19 ANKLE2 Zornitza Stark edited their review of gene: ANKLE2: Changed rating: GREEN
Severe microcephaly v2.19 ANKLE2 Zornitza Stark reviewed gene: ANKLE2: Rating: ; Mode of pathogenicity: None; Publications: 25259927, 30214071, 31735666; Phenotypes: Microcephaly 16, primary, autosomal recessive, MIM# 616681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 AGMO Zornitza Stark reviewed gene: AGMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555905; Phenotypes: microcephaly, intellectual disability, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32424323; Phenotypes: Congenital Disorder of Glycosylation, Type Iq (OMIM: 612379), Kahrizi Syndrome (OMIM: 612713); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer Deleted their review
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer changed review comment from: Comment on rating: At least 38 genetically confirmed patients (from 26 families) have been reported. The frequency and prevalence of the disease are not known. Most patients have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico, and Turkey.

Comment on the mode of pathogenicity: Loss-of-function; At least 15 variants have been reported: 11 nonsense variants, 3 missense variants, and a large deletion (www.lovd.nl/SRD5A3).

Comment on the mode of inheritance: AR (homozygous or compound heterozygous); to: Comment on rating: At least 38 genetically confirmed patients (from 26 families) have been reported. The frequency and prevalence of the disease are not known. Most patients have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico, and Turkey.

Comment on the mode of pathogenicity: Loss-of-function; At least 15 variants have been reported: 11 nonsense variants, 3 missense variants, and a large deletion (www.lovd.nl/SRD5A3).

Comment on the mode of inheritance: AR (homozygous or compound heterozygous)
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32424323; Phenotypes: Congenital Disorder of Glycosylation, Type Iq (OMIM: 612379 ), Kahrizi Syndrome (OMIM: 612713); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.6 IKZF5 Carl Fratter reviewed gene: IKZF5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31217188, 32419556; Phenotypes: Thrombocytopenia (HP:0001873), Reduced platelet alpha granules (HP:0012528).; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.13 TMX2 Zornitza Stark reviewed gene: TMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31735293, 31586943; Phenotypes: Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity MIM#618730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.13 SNAP29 Zornitza Stark gene: SNAP29 was added
gene: SNAP29 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: SNAP29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAP29 were set to 29051910; 21073448; 30793783
Phenotypes for gene: SNAP29 were set to Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (MIM#609528)
Review for gene: SNAP29 was set to GREEN
gene: SNAP29 was marked as current diagnostic
Added comment: Associated with CEDNIK syndrome. Both pachygyria and polymicrogyria, and additionally dysgenesis of the corpus callosum, are reported in multiple patients from unrelated families with pathogenic variants in this gene (at least 5 patients from 3 families with both pachygyria and polymicrogyria, and at least 5 patients from 3 families with polymicrogyria alone (PMID: 29051910, 30793783)).
Sources: Expert list
Malformations of cortical development v2.13 SCN3A Zornitza Stark gene: SCN3A was added
gene: SCN3A was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: SCN3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN3A were set to 32515017; 30146301
Phenotypes for gene: SCN3A were set to Polymicrogyria; malformations of cortical development; epilepsy
Review for gene: SCN3A was set to GREEN
gene: SCN3A was marked as current diagnostic
Added comment: Six unrelated families reported with prominent speech and oral motor dysfunction but no epilepsy, some multiplex in PMID: 30146301. Additionally malformations of cortical development reported in ~75% of a cohort of 22 individuals with a broader neurodevelomental phenotype, including epilepsy, PMID: 32515017
Sources: Expert list
Malformations of cortical development v2.13 RAB3GAP2 Zornitza Stark gene: RAB3GAP2 was added
gene: RAB3GAP2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: RAB3GAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB3GAP2 were set to 23420520; 20967465
Phenotypes for gene: RAB3GAP2 were set to Warburg micro syndrome 2, MIM# 614225
Review for gene: RAB3GAP2 was set to GREEN
gene: RAB3GAP2 was marked as current diagnostic
Added comment: Polymicrogyria is a well described phenotypic feature in Micro syndrome caused by variants in RAB3GAP2 and other genes.

PMID: 23420520 – at least 3 unrelated families with polymicrogyria
PMID: 20967465 - single proband with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 RAB3GAP1 Zornitza Stark gene: RAB3GAP1 was added
gene: RAB3GAP1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: RAB3GAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB3GAP1 were set to 23420520
Phenotypes for gene: RAB3GAP1 were set to Warburg micro syndrome 1, MIM# 600118
Review for gene: RAB3GAP1 was set to GREEN
gene: RAB3GAP1 was marked as current diagnostic
Added comment: Polymicrogyria is a well described phenotypic feature of Micro syndrome, caused by RAB3GAP1 and other genes.

PMID: 23420520 - at least 4 unrelated families with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 RAB18 Zornitza Stark gene: RAB18 was added
gene: RAB18 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: RAB18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB18 were set to 21473985; 23420520
Phenotypes for gene: RAB18 were set to Warburg micro syndrome 3, MIM# 614222
Review for gene: RAB18 was set to GREEN
Added comment: Polymicrogyria is a well described phenotypic feature in Micro syndrome, caused by RAB18 and other genes.

PMID: 21473985 – two unrelated families with polymicrogyria
PMID: 23420520 – one proband with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 PTEN Zornitza Stark gene: PTEN was added
gene: PTEN was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTEN were set to 32162846
Phenotypes for gene: PTEN were set to Cowden syndrome 1 158350; Lhermitte-Duclos syndrome 158350; Macrocephaly/autism syndrome 605309
Review for gene: PTEN was set to GREEN
gene: PTEN was marked as current diagnostic
Added comment: PMID: 32162846 - 4 unrelated individuals with PTEN variants with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 PI4KA Zornitza Stark gene: PI4KA was added
gene: PI4KA was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531
Review for gene: PI4KA was set to AMBER
Added comment: One family reported, we are aware of additional cases.
Sources: Expert list
Malformations of cortical development v2.13 NPRL3 Zornitza Stark gene: NPRL3 was added
gene: NPRL3 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: NPRL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPRL3 were set to 27173016; 26285051
Phenotypes for gene: NPRL3 were set to Epilepsy, familial focal, with variable foci 3 (MIM#617118)
Review for gene: NPRL3 was set to GREEN
Added comment: Three families reported where focal cortical dysplasia is a feature, but also reduced penetrance noted. Borderline Amber/Green.
Sources: Expert list
Malformations of cortical development v2.13 NPRL2 Zornitza Stark gene: NPRL2 was added
gene: NPRL2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: NPRL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPRL2 were set to 29281825; 27173016; 31625153
Phenotypes for gene: NPRL2 were set to Epilepsy, familial focal, with variable foci 2, MIM# 617116
Review for gene: NPRL2 was set to AMBER
Added comment: Focal cortical dysplasia reported in some patients

PMID: 29281825 (2017) - LOF variant identified in a patient with left frontal focal cortical dysplasia

PMID: 27173016 (2016) - cohort of focal epilepsy patients. LOF function variant in a family with focal epilepsy and focal cortical dysplasia. Segregated with two affected individuals but reduced penetrance and variable expressivity was observed.

Summary: associated with focal cortical dysplasia in two families. Recent review (PMID: 31625153) also states, mutations in NPRL2 have been linked to focal epilepsy with a less clear association with Focal Cortical Dysplasia.
Sources: Expert list
Malformations of cortical development v2.13 MAPK8IP3 Zornitza Stark gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30612693
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities OMIM# 605431
Review for gene: MAPK8IP3 was set to GREEN
gene: MAPK8IP3 was marked as current diagnostic
Added comment: 13 unrelated individuals reported, with de novo truncating or missense variants (one recurrent). Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants.
Sources: Expert list
Malformations of cortical development v2.13 MAP1B Zornitza Stark gene: MAP1B was added
gene: MAP1B was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to 31317654; 30150678; 30214071
Phenotypes for gene: MAP1B were set to Periventricular nodular heterotopia 9, MIM# 618918
Review for gene: MAP1B was set to GREEN
gene: MAP1B was marked as current diagnostic
Added comment: At least 5 families described with intellectual disability and variable brain malformation phenotypes.
Sources: Expert list
Malformations of cortical development v2.13 LAMA2 Zornitza Stark gene: LAMA2 was added
gene: LAMA2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: LAMA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA2 were set to 20207543; 18406646
Phenotypes for gene: LAMA2 were set to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855
Review for gene: LAMA2 was set to GREEN
gene: LAMA2 was marked as current diagnostic
Added comment: Malformations of cortical development are seen in a small proportion of individuals with biallelic LAMA2 variants. These were initially described and characterised based on immunohistochemistry showing loss of the protein associated with LAMA2. Reports where genotyping has been performed include: PMID: 20207543 – 7 individuals with biallelic LAMA2 variants and occipital agyria / polymicrogyria with a further 2 individuals with cortical folding abnormalities in other sites. PMID: 18406646 – 1 individual with a homozygous nonsense LAMA2 variant with extensive bilateral occipital polymicrogyria.
Sources: Expert list
Malformations of cortical development v2.13 GRIN2B Zornitza Stark gene: GRIN2B was added
gene: GRIN2B was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: GRIN2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GRIN2B were set to 28377535
Phenotypes for gene: GRIN2B were set to Mental retardation, autosomal dominant 6, MIM# 613970
Review for gene: GRIN2B was set to GREEN
Added comment: PMID: 28377535 - Neuroimaging was performed in 44 of 58 individuals: six unrelated individuals (6/44, 14%) showed a consistent MCD intermediate between typical polymicrogyria (PMG) and the cortical appearance of tubulinopathies, consisting of mixed large and small gyri separated by shallow sulci, a smooth grey-white border and little infolding. These individuals also had hypoplastic corpus callosum of varying degrees, enlarged and mildly dysplastic basal ganglia, hippocampal dysplasia with thick leaves and open hilus as well as enlarged tecta. One had no septum pellucidum. Generalised cerebral volume loss, compatible with cerebral atrophy, was described in four additional patients (4/44; 9%).
Sources: Expert list
Malformations of cortical development v2.13 GRIN1 Zornitza Stark gene: GRIN1 was added
gene: GRIN1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: GRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GRIN1 were set to 29365063
Phenotypes for gene: GRIN1 were set to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254
Review for gene: GRIN1 was set to GREEN
gene: GRIN1 was marked as current diagnostic
Added comment: PMID: 29365063 - series of 11 unrelated individuals with GRIN1 variants and polymicrogyria
Sources: Expert list
Intellectual disability v3.274 HARS Zornitza Stark edited their review of gene: HARS: Changed publications: 32333447
Likely inborn error of metabolism v2.17 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Likely inborn error of metabolism v2.17 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Likely inborn error of metabolism v2.17 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.16 TKFC Arina Puzriakova gene: TKFC was added
gene: TKFC was added to Inborn errors of metabolism. Sources: Literature
watchlist tags were added to gene: TKFC.
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446
Phenotypes for gene: TKFC were set to Triokinase and FMN cyclase deficiency syndrome, 618805
Review for gene: TKFC was set to AMBER
Added comment: Associated with phenotype in OMIM, and a possible gene for TKFC-related Cataracts and Multisystem Disease in G2P.

PMID: 32004446 (2020) - Two sib pairs from two unrelated consanguineous families with an inborn error of metabolism caused by distinct homozygous variants in TKFC. In Family 1, both sibs had congenital cataracts but otherwise presented disparate phenotypes. The older sister had DD (motor and speech) and cerebellar hypoplasia; while the younger sister had liver dysfunction and fatal cardiomyopathy at 11 weeks with severe lactic acidosis following a febrile illness. In Family 2, the brother exhibited global DD as well as bilateral cataracts at 22 months. He developed progressive non-cholestatic liver failure, and at 3yrs-10months he could not walk independently and had no words. His older sister, had delayed speech development and learning difficulties, but is otherwise well and did not have cataracts.

Both variants segregated with disease in each family, and some functional data of the variants using yeast cells.
Sources: Literature
Intellectual disability v3.274 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Intellectual disability v3.274 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Intellectual disability v3.274 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.273 TKFC Arina Puzriakova Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, 618805
Intellectual disability v3.272 TKFC Arina Puzriakova Tag watchlist tag was added to gene: TKFC.
Intellectual disability v3.272 TKFC Arina Puzriakova reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004446; Phenotypes: Triokinase and FMN cyclase deficiency syndrome, 618805; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.13 TKFC Arina Puzriakova Tag watchlist tag was added to gene: TKFC.
Bilateral congenital or childhood onset cataracts v2.13 TKFC Arina Puzriakova Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, 618805
Bilateral congenital or childhood onset cataracts v2.12 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.12 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Bilateral congenital or childhood onset cataracts v2.12 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.11 TKFC Arina Puzriakova reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004446; Phenotypes: Triokinase and FMN cyclase deficiency syndrome, 618805; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.272 TP73 Arina Puzriakova Classified gene: TP73 as Red List (low evidence)
Intellectual disability v3.272 TP73 Arina Puzriakova Added comment: Comment on list classification: Rating Red as gene only distinguished due to multiple hits in same candidate gene - patients display discordant phenotype and DD only reported in one patient.
Intellectual disability v3.272 TP73 Arina Puzriakova Gene: tp73 has been classified as Red List (Low Evidence).
Intellectual disability v3.271 TP73 Arina Puzriakova reviewed gene: TP73: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.271 SMG8 Arina Puzriakova Classified gene: SMG8 as Red List (low evidence)
Intellectual disability v3.271 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Red as gene only distinguished due to multiple hits in same candidate gene; however, patients display discordant phenotype and ID only reported in one patient.
Intellectual disability v3.271 SMG8 Arina Puzriakova Gene: smg8 has been classified as Red List (Low Evidence).
Intellectual disability v3.270 SMG8 Arina Puzriakova reviewed gene: SMG8: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Tag founder-effect tag was added to gene: RAP1GDS1.
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Classified gene: RAP1GDS1 as Red List (low evidence)
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Added comment: Comment on list classification: The same variant identified in two families from the region, indicating a possible founder effect. Therefore rated Red as there is not currently enough evidence that other variants in the RAP1GDS1 gene are disease causing.
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Gene: rap1gds1 has been classified as Red List (Low Evidence).
Intellectual disability v3.269 RAP1GDS1 Arina Puzriakova reviewed gene: RAP1GDS1: Rating: ; Mode of pathogenicity: None; Publications: 32431071; Phenotypes: Intellectual disability, Global developmental delay, Hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Classified gene: PDCD6IP as Amber List (moderate evidence)
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Gene: pdcd6ip has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least four unrelated individuals with three distinct TUBGCP2 variants, associated with generalised seizures.
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.145 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), generalised seizures (4/5, onset at 6yrs-9m, 5m, and 7m). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least three families with distinct TUBGCP2 variants, presenting progressive severe microcephaly.
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.18 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive severe microcephaly (4/4, Z score: -4.0 to -9.0), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova changed review comment from: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).; to: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy/Microcephaly), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Malformations of cortical development v2.13 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 18758830; 24598713
Phenotypes for gene: FIG4 were set to Polymicrogyria with epilepsy MIM# 612691
Review for gene: FIG4 was set to AMBER
Added comment: One family and a supportive mouse model:

PMID 18758830 – Ben Cheikh et al (2009) studied a large consanguineous Moroccan family in which bilateral occipital polymicrogyria segregated as an autosomal recessive trait, establishing linkage to 6q16-q22 by homozygosity mapping. Three affected individuals had epilepsy and polymicrogyria (other siblings had variable phenotypes).

PMID 24598713 – Baulac et al (2014) analysed the consanguineous Moroccan family and detected a homozygous missense variant in FIG4, which was homozygous in each of the affected siblings with polymicrogyria, heterozygous in one healthy sibling, not present in three healthy siblings, heterozygous in both parents and not tested in a further four siblings. They went on to study transfected fibroblasts from FIG4 deficient mice and examined histologically brains from FIG4-null mice which had findings that included changes “reminiscent of human cortical malformations”.
Sources: Expert list
Malformations of cortical development v2.13 FAT4 Zornitza Stark gene: FAT4 was added
gene: FAT4 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: FAT4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT4 were set to 22473091; 24056717
Phenotypes for gene: FAT4 were set to Van Maldergem syndrome 2, MIM# 615546
Review for gene: FAT4 was set to AMBER
Added comment: PVNH reported in two families.
Sources: Expert list
Malformations of cortical development v2.13 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Malformations of cortical development v2.13 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least four families with three distinct TUBGCP2 variants, associated with a lissencephaly-spectrum phenotype.
Malformations of cortical development v2.13 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.12 TUBGCP2 Arina Puzriakova Tag for-review tag was added to gene: TUBGCP2.
Malformations of cortical development v2.12 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Deleted their comment
Malformations of cortical development v2.11 EML1 Zornitza Stark gene: EML1 was added
gene: EML1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: EML1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EML1 were set to 31710781
Phenotypes for gene: EML1 were set to Band heterotopia (MIM# 600348)
Review for gene: EML1 was set to GREEN
gene: EML1 was marked as current diagnostic
Added comment: PMID: 31710781; Review of 5 families with patients characterised by severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging of 4 patients, there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation.
Sources: Expert list
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as No list
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been removed from the panel.
Malformations of cortical development v2.11 DEPDC5 Zornitza Stark gene: DEPDC5 was added
gene: DEPDC5 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: DEPDC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DEPDC5 were set to 31444548
Phenotypes for gene: DEPDC5 were set to Epilepsy, familial focal, with variable foci 1 (MIM#604364)
Review for gene: DEPDC5 was set to GREEN
gene: DEPDC5 was marked as current diagnostic
Added comment: PMID: 31444548
- 5x focal cortical dysplasia patients
Sources: Expert list
Malformations of cortical development v2.11 DCHS1 Zornitza Stark gene: DCHS1 was added
gene: DCHS1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: DCHS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCHS1 were set to 27262615; 22473091
Phenotypes for gene: DCHS1 were set to Van Maldergem syndrome 1 (MIM#601390)
Review for gene: DCHS1 was set to GREEN
gene: DCHS1 was marked as current diagnostic
Added comment: PMID: 27262615;
- cohort of 26x periventricular band heterotopias and 2x had additional phenotype of pachygyria
- 2nd cohort of 10x band heterotopias

PMID: 22473091;
- 1x patient with localised areas of cortical thickening and gyral simplification
Sources: Literature
Sources: Expert list
Malformations of cortical development v2.11 DAG1 Zornitza Stark reviewed gene: DAG1: Rating: RED; Mode of pathogenicity: None; Publications: 24052401; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9 (MIM#616538); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.11 CTNNA2 Zornitza Stark gene: CTNNA2 was added
gene: CTNNA2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNA2 were set to 30013181
Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9, MIM#618174
Review for gene: CTNNA2 was set to GREEN
gene: CTNNA2 was marked as current diagnostic
Added comment: 13 children from three unrelated families reported.
Sources: Expert list
Intellectual disability v3.267 TUBGCP2 Arina Puzriakova Tag watchlist tag was added to gene: TUBGCP2.
Intellectual disability v3.267 TUBGCP2 Arina Puzriakova reviewed gene: TUBGCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31630790; Phenotypes: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.11 CSNK2A1 Zornitza Stark reviewed gene: CSNK2A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27048600, 29240241; Phenotypes: Okur-Chung neurodevelopmental syndrome (MIM#617062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.11 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Malformations of cortical development v2.11 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 5 unrelated cases reported with brain malformations associated with PPP1R12A variants.

PPP1R12A has been added to this panel following discussion with the clinical team.
Malformations of cortical development v2.11 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.10 PPP1R12A Arina Puzriakova gene: PPP1R12A was added
gene: PPP1R12A was added to Malformations of cortical development. Sources: Literature
for-review tags were added to gene: PPP1R12A.
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Genitourinary and/or/brain malformation syndrome, 618820
Review for gene: PPP1R12A was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 5/12 individuals presented structural CNS anomalies; however, the phenotype was variable and included dysgenesis of the corpus callosum, polymicrogyria, leukomalacia, and acrania.
Sources: Literature
Differences in sex development v2.6 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Differences in sex development v2.6 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with significant genitourinary malformations.
Differences in sex development v2.6 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.5 PPP1R12A Arina Puzriakova gene: PPP1R12A was added
gene: PPP1R12A was added to Disorders of sex development. Sources: Literature
for-review tags were added to gene: PPP1R12A.
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Genitourinary and/or/brain malformation syndrome, 618820
Review for gene: PPP1R12A was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). Out of the 12 patients, 4 were XY females and 3 were XY males with significant anomalies.
Sources: Literature
Holoprosencephaly v2.7 PPP1R12A Arina Puzriakova Phenotypes for gene: PPP1R12A were changed from Intellectual disability; holoprosencephaly; disorder of sex development to Genitourinary and/or/brain malformation syndrome, 618820
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Tag watchlist tag was added to gene: PPP1R12A.
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further publications/clinical evidence as currently only two cases reported (added to watchlist).
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.5 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.267 PPP1R12A Arina Puzriakova Phenotypes for gene: PPP1R12A were changed from Intellectual disability; holoprosencephaly; disorder of sex development to Genitourinary and/or/brain malformation syndrome, 618820
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - DD reported in at least 7 unrelated patients with PPP1R12A variants.
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.265 PPP1R12A Arina Puzriakova Tag for-review tag was added to gene: PPP1R12A.