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Fetal anomalies v1.930 DEPDC5 Arina Puzriakova Classified gene: DEPDC5 as Amber List (moderate evidence)
Fetal anomalies v1.930 DEPDC5 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.930 DEPDC5 Arina Puzriakova Gene: depdc5 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.929 DEPDC5 Arina Puzriakova Publications for gene: DEPDC5 were set to
Fetal anomalies v1.928 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from FAMILIAL FOCAL EPILEPSY WITH VARIABLE FOCI to Epilepsy; Structural brain malformations
Fetal anomalies v1.927 DEPDC5 Arina Puzriakova Mode of inheritance for gene: DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v1.40 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v1.40 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene can now be promoted to Green status at the next GMS review.
Unexplained young onset end-stage renal disease v1.40 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v1.39 CHRM3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: CHRM3.
Unexplained kidney failure in young people v1.116 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Green List (high evidence)
Unexplained kidney failure in young people v1.116 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene has now been promoted to Green status.
Unexplained kidney failure in young people v1.116 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Green List (High Evidence).
CAKUT v1.172 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Green List (high evidence)
CAKUT v1.172 CHRM3 Arina Puzriakova Added comment: Comment on list classification: Two unrelated families with urinary bladder disease (PMIDs: 22077972; 31441039) have now been published (including the one previously reviewed by Adrian Woolf in 2016), and given that the null mutant mouse model recapitulates the human phenotype (PMID: 10944224), this gene has now been promoted to Green status.
CAKUT v1.172 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.115 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune Belly-Like Syndrome; Low pressure congenital megabladder to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
Unexplained young onset end-stage renal disease v1.39 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Low pressure congenital megabladder; Prune Belly-Like Syndrome to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
Unexplained kidney failure in young people v1.114 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altm ller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, N rnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
Unexplained young onset end-stage renal disease v1.38 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altm ller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, N rnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
CAKUT v1.171 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altmüller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, Nürnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome. Am J Hum Genet 89:668-674, 2011.
Fetal anomalies v1.926 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to 22077972; 31441039; 10944224
CAKUT v1.170 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune Belly-Like Syndrome; Low pressure congenital megabladder to Prune belly syndrome, OMIM:100100; Megacystis; Urinary Bladder Disease
Fetal anomalies v1.925 CHRM3 Arina Puzriakova Classified gene: CHRM3 as Amber List (moderate evidence)
Fetal anomalies v1.925 CHRM3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.925 CHRM3 Arina Puzriakova Gene: chrm3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.924 CHRM3 Arina Puzriakova Phenotypes for gene: CHRM3 were changed from Prune belly syndrome; Megacystis to Prune belly syndrome, OMIM:100100; Megacystis
Fetal anomalies v1.923 CHRM3 Arina Puzriakova Publications for gene: CHRM3 were set to PMID: 22077972; 31441039; 10944224
Fetal anomalies v1.922 CACNA1S Arina Puzriakova Publications for gene: CACNA1S were set to PMID: 33060286; 28012042
Fetal anomalies v1.921 CACNA1S Arina Puzriakova Classified gene: CACNA1S as Amber List (moderate evidence)
Fetal anomalies v1.921 CACNA1S Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.921 CACNA1S Arina Puzriakova Gene: cacna1s has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.920 CACNA1D Arina Puzriakova Mode of pathogenicity for gene: CACNA1D was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v1.919 CACNA1D Arina Puzriakova Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.918 CACNA1D Arina Puzriakova Publications for gene: CACNA1D were set to
Fetal anomalies v1.917 CACNA1D Arina Puzriakova Phenotypes for gene: CACNA1D were changed from PRIMARY ALDOSTERONISM, SEIZURES, AND NEUROLOGIC ABNORMALITIES; SINOATRIAL NODE DYSFUNCTION AND DEAFNESS to Primary aldosteronism, seizures, and neurologic abnormalities, OMIM:615474
Fetal anomalies v1.916 C1QBP Arina Puzriakova Phenotypes for gene: C1QBP were changed from Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies to Combined oxidative phosphorylation deficiency 33, OMIM:617713; Cardiomyopathy; Myopathy; Metabolic acidosis; Ologohydramnios
Fetal anomalies v1.915 C1QBP Arina Puzriakova Publications for gene: C1QBP were set to
Fetal anomalies v1.914 ASXL3 Arina Puzriakova Phenotypes for gene: ASXL3 were changed from BAINBRIDGE-ROPERS SYNDROME to Bainbridge-Ropers syndrome, OMIM:615485; Arthrogryposis
Fetal anomalies v1.913 ASXL3 Arina Puzriakova Publications for gene: ASXL3 were set to
Fetal anomalies v1.912 ASPH Arina Puzriakova Publications for gene: ASPH were set to
Fetal anomalies v1.911 AGT Arina Puzriakova Classified gene: AGT as Amber List (moderate evidence)
Fetal anomalies v1.911 AGT Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.911 AGT Arina Puzriakova Gene: agt has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.910 AGT Arina Puzriakova Publications for gene: AGT were set to PMID: 28976722
Fetal anomalies v1.909 AGT Arina Puzriakova Phenotypes for gene: AGT were changed from Renal dysgenesis to Renal tubular dysgenesis, OMIM:267430
Fetal anomalies v1.908 ACVRL1 Arina Puzriakova Publications for gene: ACVRL1 were set to
Fetal anomalies v1.907 ACVRL1 Arina Puzriakova Phenotypes for gene: ACVRL1 were changed from Telangiectasia, hereditary hemorrhagic, type 2 600376 to Telangiectasia, hereditary hemorrhagic, type 2, OMIM:600376
Fetal anomalies v1.906 ACVRL1 Arina Puzriakova Classified gene: ACVRL1 as Amber List (moderate evidence)
Fetal anomalies v1.906 ACVRL1 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.906 ACVRL1 Arina Puzriakova Gene: acvrl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1677 TAF4 Konstantinos Varvagiannis reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904126; Phenotypes: Delayed speech and language development, Intellectual disability, Behavioral abnormality, Joint laxity, Abnormality of the vertebral column, Abnormality of nervous system morphology, Abnormality of head or neck; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1677 ZMYND8 Konstantinos Varvagiannis gene: ZMYND8 was added
gene: ZMYND8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND8 were set to unknown
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

----

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

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

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

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

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

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

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

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

----

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

17 individuals from 14 unrelated families

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

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

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

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

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

17 individuals from 14 unrelated families

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

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

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

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

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

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

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

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

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

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

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

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

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

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

-----

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 c.142A>T; p.(Lys48*) in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. No loss of hearing was noted.
Intellectual disability v3.1590 MED13 Catherine Snow Tag Q2_22_rating tag was added to gene: MED13.
Tag Q2_22_NHS_review tag was added to gene: MED13.
Intellectual disability v3.1590 MED13 Catherine Snow reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33931951; Phenotypes: Intellectual developmental disorder, autosomal dominant 61 OMIM:618009; Mode of inheritance: None
Renal tubulopathies v2.54 SEC61A1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: SEC61A1.
Tag Q2_21_expert_review was removed from gene: SEC61A1.
Tag Q2_22_phenotype tag was added to gene: SEC61A1.
Tag Q2_22_expert_review tag was added to gene: SEC61A1.
Renal tubulopathies v2.54 SEC61A1 Eleanor Williams Tag Q2_21_phenotype tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 HCK Boaz Palterer gene: HCK was added
gene: HCK was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: HCK was set to Unknown
Publications for gene: HCK were set to 34536415
Phenotypes for gene: HCK were set to Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease
Penetrance for gene: HCK were set to unknown
Mode of pathogenicity for gene: HCK was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: HCK was set to RED
Added comment: Kanderova et al. described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis.
A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified.
Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines.
Sources: Literature
Retinal disorders v2.272 SLC38A8 Eleanor Williams commented on gene: SLC38A8: Green review from Mohammed Derar on green gene so no change in rating needed. Phenotypes updated.
Retinal disorders v2.272 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216 to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; chiasmal misrouting
DDG2P v2.72 FGF5 Eleanor Williams commented on gene: FGF5
DDG2P v2.72 PLCB4 Eleanor Williams commented on gene: PLCB4
Fetal anomalies v1.862 PLCB4 Eleanor Williams Classified gene: PLCB4 as Amber List (moderate evidence)
Fetal anomalies v1.862 PLCB4 Eleanor Williams Added comment: Comment on list classification: Leaving the rating of this gene as amber just now, but there are sufficient cases to promote to green following GMS review.
Fetal anomalies v1.862 PLCB4 Eleanor Williams Gene: plcb4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.861 PLCB4 Eleanor Williams Mode of inheritance for gene: PLCB4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.860 PLCB4 Eleanor Williams Tag Q2_22_rating tag was added to gene: PLCB4.
Fetal anomalies v1.860 PLCB4 Eleanor Williams reviewed gene: PLCB4: Rating: ; Mode of pathogenicity: None; Publications: 22560091, 23315542, 28328130, 23913798; Phenotypes: Auriculocondylar syndrome 2, OMIM:614669, auriculocondylar syndrome 2, MONDO:0013845; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting v2.68 PLCB4 Eleanor Williams Tag Q2_22_rating tag was added to gene: PLCB4.
Clefting v2.68 PLCB4 Eleanor Williams edited their review of gene: PLCB4: Added comment: PMID: 28328130 - Romanelli-Tavares et al 2017 - report 2 patients (1 sporadic, 1 familial) with previous published phenotypic descriptions of Auriculocondylar syndrome in which heterozygous missense variants were found in PLCB4 after sequencing PLCB4, GNAI3,and EDN1. Cleft palate was noted in 2/7 members of the familial case.

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

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

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

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

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

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

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

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

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

-----

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

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

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

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

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

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

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

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

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

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

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

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

-----

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

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

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

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

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

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

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

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

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].
Intellectual disability v3.1580 SRRM2 Konstantinos Varvagiannis reviewed gene: SRRM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35567594, 33057194; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of the head or neck, Small hand, Short foot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hypertrophic cardiomyopathy v2.38 ALPK3 Luis Lopes reviewed gene: ALPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34263907, 35583889; Phenotypes: Hypertrophic Cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.524 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

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

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

-----

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

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

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

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

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

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

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

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

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

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

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

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

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Intellectual disability v3.1580 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

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

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

-----

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID:33840812 - Webb et al 2021 - report a homozygous loss-of-function variant identified by WES in KCNJ16 in a 2-year-old female with a hypokalemic metabolic acidosis phenotype. Hearing loss is NOT mentioned.
Sources: Literature
Renal tubulopathies v2.54 SEC61A1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel. There are sufficient cases with Autosomal dominant tubulointerstitial kidney to rate green.; to: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the associated disease phenotype fulfils the eligibility criteria for this panel. There are sufficient cases with Autosomal dominant tubulointerstitial kidney to rate green.
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams Classified gene: KCNJ16 as Amber List (moderate evidence)
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber with a recommendation of green rating following GMS review.
Renal tubulopathies v2.54 KCNJ16 Eleanor Williams Gene: kcnj16 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.53 KCNJ16 Eleanor Williams Tag Q2_22_rating tag was added to gene: KCNJ16.
Renal tubulopathies v2.53 KCNJ16 Eleanor Williams Phenotypes for gene: KCNJ16 were changed from Renal tubulopathy; deafness to Hypokalemic tubulopathy and deafness, OMIM:619406
Renal tubulopathies v2.52 KCNJ16 Eleanor Williams commented on gene: KCNJ16
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel; to: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel. There are sufficient cases with Autosomal dominant tubulointerstitial kidney to rate green.
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams Classified gene: SEC61A1 as Amber List (moderate evidence)
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. This gene should be reviewed to whether the phenotype is appropriate to this panel
Renal tubulopathies v2.52 SEC61A1 Eleanor Williams Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.51 SEC61A1 Eleanor Williams Publications for gene: SEC61A1 were set to PMID: 33185949; 27392076; 31488840
Renal tubulopathies v2.50 SEC61A1 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: SEC61A1.
Tag Q2_22_rating tag was added to gene: SEC61A1.
Renal tubulopathies v2.50 SEC61A1 Eleanor Williams reviewed gene: SEC61A1: Rating: ; Mode of pathogenicity: None; Publications: 33185949, 30586318, 27392076, 31488840; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.45 IFT140 Eleanor Williams Tag Q2_22_NHS_review tag was added to gene: IFT140.
Cystic kidney disease v2.45 IFT140 Eleanor Williams Tag Q2_22_rating tag was added to gene: IFT140.
Cystic kidney disease v2.45 IFT140 Eleanor Williams Classified gene: IFT140 as Amber List (moderate evidence)
Cystic kidney disease v2.45 IFT140 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber with a recommendation for GREEN rating following GMS review.
Cystic kidney disease v2.45 IFT140 Eleanor Williams Gene: ift140 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.44 IFT140 Eleanor Williams Phenotypes for gene: IFT140 were changed from Cystic kidney disease; chronic kidney disease to Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964; cystic kidney disease, MONDO:0002473
Cystic kidney disease v2.43 IFT140 Eleanor Williams Publications for gene: IFT140 were set to 34890546
Cystic kidney disease v2.42 IFT140 Eleanor Williams Added comment: Comment on mode of inheritance: As reviewer notes there are several biallelic cases reported with a renal phenotype (e.g. PMID: 23418020 - 3 patients with renal cysts and biallelic IFT140 variants, PMID: 27874174 - 1 patient with renal cysts and biallelic IFT140 variants) aswell as the monallelic variants reported in PMID:34890546
Cystic kidney disease v2.42 IFT140 Eleanor Williams Mode of inheritance for gene: IFT140 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1580 SCAF4 Ian Berry reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32730804; Phenotypes: Seizures, intellectual disability (mild); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.143 SOX11 Sarah Leigh edited their review of gene: SOX11: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. SOX11 variants have been reported by the NHS, including one from Tracy Lester and de novo variants in around 20 children with overlapping clinical features by Alisdair mcneill (Sheffield childrens hospital)(7 Oct 2019).; Changed rating: GREEN
Malformations of cortical development v2.143 SOX11 Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405).
Malformations of cortical development v2.143 SOX11 Sarah Leigh Phenotypes for gene: SOX11 were changed from intellectual disability; facial dysmorphism; microcephaly; digit anomalies; central nervous system malformations to Coffin-Siris syndrome 9, OMIM:615866
Intellectual disability v3.1580 SOX11 Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405).
Intellectual disability v3.1580 SOX11 Sarah Leigh Phenotypes for gene: SOX11 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 to Coffin-Siris syndrome 9, OMIM:615866
Intellectual disability v3.1579 SOX11 Sarah Leigh Publications for gene: SOX11 were set to 24886874
Malformations of cortical development v2.142 SOX11 Sarah Leigh Classified gene: SOX11 as Amber List (moderate evidence)
Malformations of cortical development v2.142 SOX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.142 SOX11 Sarah Leigh Gene: sox11 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.141 SOX11 Sarah Leigh Tag Q2_22_rating tag was added to gene: SOX11.
Tag Q2_22_NHS_review tag was added to gene: SOX11.
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh edited their review of gene: SLC5A6: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 6 variants have been reported in at least 4 unrelated cases. Supportive functional studies and targeted therapeutic interventionyielded clinical improvement in four of the five patients (PMID: 35013551).; Changed rating: GREEN; Changed publications to: 35013551; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Tag Q2_21_NHS_review tag was added to gene: SLC5A6.
Tag Q2_22_rating tag was added to gene: SLC5A6.
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.102 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to PMID: 35013551
Early onset or syndromic epilepsy v2.524 PRODH Sarah Leigh commented on gene: PRODH: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).
Early onset or syndromic epilepsy v2.524 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I 239500 to Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400
Likely inborn error of metabolism v2.255 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I 239500; Hyperprolinaemia type I (Disorders of ornithine or proline metabolism) to Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400
Likely inborn error of metabolism v2.254 PRODH Sarah Leigh Classified gene: PRODH as Green List (high evidence)
Likely inborn error of metabolism v2.254 PRODH Sarah Leigh Added comment: Comment on list classification: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).
Likely inborn error of metabolism v2.254 PRODH Sarah Leigh Gene: prodh has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.534 PRODH Sarah Leigh Classified gene: PRODH as Green List (high evidence)
Undiagnosed metabolic disorders v1.534 PRODH Sarah Leigh Added comment: Comment on list classification: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).
Undiagnosed metabolic disorders v1.534 PRODH Sarah Leigh Gene: prodh has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.533 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinaemia type I (Disorders of ornithine or proline metabolism); Hyperprolinemia, type I 239500 to Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400
Intellectual disability v3.1578 PRODH Sarah Leigh edited their review of gene: PRODH: Added comment: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).; Changed rating: GREEN; Changed phenotypes to: Hyperprolinemia, type I, OMIM, 239500, hyperprolinemia type 1, MONDO:0009400
Intellectual disability v3.1578 PRODH Sarah Leigh Tag Q2_22_NHS_review tag was added to gene: PRODH.
Intellectual disability v3.1578 PRODH Sarah Leigh Tag Q2_22_rating tag was added to gene: PRODH.
Tag Q2_22_expert_review tag was added to gene: PRODH.
Intellectual disability v3.1578 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, 239500; {Schizophrenia, susceptibility to, 4}, 600850 to Hyperprolinemia, type I, OMIM; 239500; {Schizophrenia, susceptibility to, OMIM:4}, 600850
Intellectual disability v3.1577 PRODH Sarah Leigh Publications for gene: PRODH were set to 12217952
Intellectual disability v3.1576 PRPF8 Konstantinos Varvagiannis gene: PRPF8 was added
gene: PRPF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 35543142
Phenotypes for gene: PRPF8 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059
Penetrance for gene: PRPF8 were set to unknown
Review for gene: PRPF8 was set to AMBER
Added comment: A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies.

Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) .

Overall consider inclusion with amber rating.

------

O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8.

Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y).

PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided).

Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data).

13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available.

PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD.

Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance.

As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins.

Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain).

There were no variant studies performed.

Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord.

The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654).
Sources: Literature
Intellectual disability v3.1576 THUMPD1 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 7 variants have been reported, together with supportive functional studies (PMID: 35196516).; to: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 8 variants have been reported in at least 7 unrelated cases, together with supportive functional studies (PMID: 35196516).
Intellectual disability v3.1576 THUMPD1 Sarah Leigh edited their review of gene: THUMPD1: Added comment: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 7 variants have been reported, together with supportive functional studies (PMID: 35196516).; Changed rating: GREEN
Intellectual disability v3.1576 THUMPD1 Sarah Leigh Added comment: Comment on phenotypes: Phenotype name based on Gen2Phen entry (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4827).
Intellectual disability v3.1576 THUMPD1 Sarah Leigh Phenotypes for gene: THUMPD1 were changed from to THUMPD1 neurodevelopment disorder
Intellectual disability v3.1575 THUMPD1 Sarah Leigh Classified gene: THUMPD1 as Amber List (moderate evidence)
Intellectual disability v3.1575 THUMPD1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1575 THUMPD1 Sarah Leigh Gene: thumpd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1574 THUMPD1 Sarah Leigh Tag Q2_22_rating tag was added to gene: THUMPD1.
Tag Q2_22_NHS_review tag was added to gene: THUMPD1.
Intellectual disability v3.1574 THUMPD1 Sarah Leigh Publications for gene: THUMPD1 were set to
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.119 ZBTB7A Sarah Leigh Phenotypes for gene: ZBTB7A were changed from intellectual disability; macrocephaly; overgrowth to Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin, OMIM:619769
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.118 ZBTB7A Sarah Leigh Publications for gene: ZBTB7A were set to 34515416
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.117 ZBTB7A Sarah Leigh Classified gene: ZBTB7A as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.117 ZBTB7A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 11 variants have been reported in 10 unrelated cases.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.117 ZBTB7A Sarah Leigh Gene: zbtb7a has been classified as Green List (High Evidence).
Intellectual disability v3.1573 ZBTB7A Sarah Leigh edited their review of gene: ZBTB7A: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 11 variants have been reported in 10 unrelated cases.; Changed rating: GREEN
Intellectual disability v3.1573 ZBTB7A Sarah Leigh Phenotypes for gene: ZBTB7A were changed from Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia to Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin, OMIM:619769
Intellectual disability v3.1572 ZBTB7A Sarah Leigh Classified gene: ZBTB7A as Amber List (moderate evidence)
Intellectual disability v3.1572 ZBTB7A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1572 ZBTB7A Sarah Leigh Gene: zbtb7a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1571 ZBTB7A Sarah Leigh Tag Q2_22_rating tag was added to gene: ZBTB7A.
Tag Q2_22_NHS_review tag was added to gene: ZBTB7A.
Early onset or syndromic epilepsy v2.523 RALGAPB Arina Puzriakova Classified gene: RALGAPB as Red List (low evidence)
Early onset or syndromic epilepsy v2.523 RALGAPB Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as this currently represents a candidate gene and only a single individual has been reported with a relevant phenotype. Primary phenotype associated with this gene has been ASD which is not within the scope of this panel.
Early onset or syndromic epilepsy v2.523 RALGAPB Arina Puzriakova Gene: ralgapb has been classified as Red List (Low Evidence).
Pain syndromes v1.12 SEPT9 Eleanor Williams commented on gene: SEPT9
Structural eye disease v1.132 ZNF408 Ivone Leong Tag Q1_22_NHS_review was removed from gene: ZNF408.
Structural eye disease v1.132 WRAP73 Ivone Leong Classified gene: WRAP73 as Red List (low evidence)
Structural eye disease v1.132 WRAP73 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on Expert review by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust)
Structural eye disease v1.132 WRAP73 Ivone Leong Gene: wrap73 has been classified as Red List (Low Evidence).
Intellectual disability v3.1571 CELF2 Arina Puzriakova Classified gene: CELF2 as Amber List (moderate evidence)
Intellectual disability v3.1571 CELF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 11 unrelated individuals harbouring heterozygous variants (10 de novo) in this gene. DD/ID observed in all cases, and although in some this was subsequent to onset of seizures, at least 2 individuals showed no epilepsy and therefore inclusion of CELF2 on this panel would be of value.
Intellectual disability v3.1571 CELF2 Arina Puzriakova Gene: celf2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.131 WRAP73 Ivone Leong Publications for gene: WRAP73 were set to PMID: 33693649
Structural eye disease v1.130 WLS Ivone Leong Classified gene: WLS as Amber List (moderate evidence)
Structural eye disease v1.130 WLS Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Structural eye disease v1.130 WLS Ivone Leong Gene: wls has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.129 WLS Ivone Leong Tag Q2_22_rating tag was added to gene: WLS.
Structural eye disease v1.129 TMEM5 Ivone Leong Classified gene: TMEM5 as Amber List (moderate evidence)
Structural eye disease v1.129 TMEM5 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Structural eye disease v1.129 TMEM5 Ivone Leong Gene: tmem5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1570 CELF2 Arina Puzriakova Tag Q2_22_rating tag was added to gene: CELF2.
Tag Q2_22_NHS_review tag was added to gene: CELF2.
Structural eye disease v1.128 TMEM5 Ivone Leong Tag Q2_22_rating tag was added to gene: TMEM5.
Tag Q2_22_NHS_review tag was added to gene: TMEM5.
Structural eye disease v1.128 TMEM5 Ivone Leong Phenotypes for gene: TMEM5 were changed from Muscular Dystrophy-Dystroglycanopathy, Type A, 10, MDDGA10, 615041 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, OMIM:615041
Structural eye disease v1.127 TMEM5 Ivone Leong Publications for gene: TMEM5 were set to
Intellectual disability v3.1570 CELF2 Arina Puzriakova Publications for gene: CELF2 were set to 34107259; 33131106
Early onset or syndromic epilepsy v2.522 CELF2 Arina Puzriakova Classified gene: CELF2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.522 CELF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 11 unrelated individuals harbouring heterozygous variants (10 de novo) in this gene. Seizures observed in 9/11 cases.
Early onset or syndromic epilepsy v2.522 CELF2 Arina Puzriakova Gene: celf2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.126 PACS1 Ivone Leong Classified gene: PACS1 as Amber List (moderate evidence)
Structural eye disease v1.126 PACS1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Structural eye disease v1.126 PACS1 Ivone Leong Gene: pacs1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.125 PACS1 Ivone Leong Tag Q2_21_rating was removed from gene: PACS1.
Tag Q1_22_NHS_review was removed from gene: PACS1.
Tag Q2_22_rating tag was added to gene: PACS1.
Tag Q2_22_NHS_review tag was added to gene: PACS1.
Structural eye disease v1.125 PACS1 Ivone Leong Tag Q2_21_rating tag was added to gene: PACS1.
Structural eye disease v1.125 HHAT Ivone Leong Classified gene: HHAT as Amber List (moderate evidence)
Structural eye disease v1.125 HHAT Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Structural eye disease v1.125 HHAT Ivone Leong Gene: hhat has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.521 CELF2 Arina Puzriakova Tag Q2_22_rating tag was added to gene: CELF2.
Tag Q2_22_NHS_review tag was added to gene: CELF2.
Early onset or syndromic epilepsy v2.521 CELF2 Arina Puzriakova Publications for gene: CELF2 were set to 33131106
Structural eye disease v1.124 HHAT Ivone Leong Tag Q2_21_rating tag was added to gene: HHAT.
Intellectual disability v3.1569 CELF2 Arina Puzriakova Phenotypes for gene: CELF2 were changed from Developmental delay; epileptic encephalopathy to Developmental and epileptic encephalopathy 97, OMIM:619561
Structural eye disease v1.124 CRIM1 Ivone Leong Tag Q2_21_NHS_review tag was added to gene: CRIM1.
Early onset or syndromic epilepsy v2.520 CELF2 Arina Puzriakova Phenotypes for gene: CELF2 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 97, OMIM:619561
Structural eye disease v1.124 CRIM1 Ivone Leong Deleted their comment
Structural eye disease v1.124 CRIM1 Ivone Leong edited their review of gene: CRIM1: Added comment: This gene is associated with a phenotype in Gene2Phenotype (limited) but not in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: AMBER
Structural eye disease v1.124 CRIM1 Ivone Leong edited their review of gene: CRIM1: Added comment: This gene is associated with a phenotype in Gene2Phenotype (limited) but not in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Structural eye disease v1.124 CRIM1 Ivone Leong Tag Q1_22_rating was removed from gene: CRIM1.
Tag Q2_22_rating tag was added to gene: CRIM1.
Structural eye disease v1.124 CRIM1 Ivone Leong Tag Q1_22_rating tag was added to gene: CRIM1.
Structural eye disease v1.124 CRIM1 Ivone Leong Publications for gene: CRIM1 were set to 25561690; 26681494
Intellectual disability v3.1568 PHF14 Dmitrijs Rots gene: PHF14 was added
gene: PHF14 was added to Intellectual disability. Sources: Literature,Expert list
Mode of inheritance for gene: PHF14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF14 were set to 35074918
Phenotypes for gene: PHF14 were set to Autism
Review for gene: PHF14 was set to GREEN
Added comment: Multiple individuals in the literature reported with NDD and de novo PHF14 variants + experimental findings (in 35074918).
Additional info from AutDB:"De novo missense variants in the PHF14 gene have been identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium cohort (Satterstrom et al., 2020), while additional rare de novo non-coding variation in this gene has also been observed in ASD probands (Sanders et al., 2015; Yuen et al., 2017). Zhou et al., 2022 reported that PHF14 forms a complex with MECP2 and TCF20; in the same report, the authors described two individuals with de novo variants in PHF14 who presented with neurodevelopmental phenotypes, including a patient with a de novo PHF14 missense variant that abolished the MECP2-PHF14-TCF20 interaction."
Sources: Literature, Expert list
Structural eye disease v1.123 FANCL Arina Puzriakova Mode of inheritance for gene: FANCL was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.549 C17orf62 Arina Puzriakova Phenotypes for gene: C17orf62 were changed from Autosomal recessive CGD EROS; Congenital defects of phagocyte number or function; Chronic granulomatous disease to Chronic granulomatous disease 5, autosomal recessive, OMIM:618935; Autosomal recessive CGD EROS; Congenital defects of phagocyte number or function; Chronic granulomatous disease
Intellectual disability v3.1568 ABCC9 Arina Puzriakova Tag watchlist_moi tag was added to gene: ABCC9.
Bleeding and platelet disorders v1.40 F7 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: F7.
Intellectual disability v3.1568 ROBO1 Konstantinos Varvagiannis gene: ROBO1 was added
gene: ROBO1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35348658; 35227688; 34193621; 31448886; 30692597; 29194579; 28592524; 28402530; 28286008
Phenotypes for gene: ROBO1 were set to ROBO1-related NDD
Penetrance for gene: ROBO1 were set to unknown
Review for gene: ROBO1 was set to AMBER
Added comment: DD/ID has been reported in some individuals with biallelic (e.g. 4 subjects in the study by Münch et al, 1 additional case reported by Calloni et al) or monoallelic ROBO1 variants (e.g. P2 in the study by Huang et al, with a diagnosis of EOEE due to a neomorphic variant).

Consider amber rating pending further review.

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Huang et al (2022 - PMID: 35348658) Monoallelic & Biallelic
Novel dominant and recessive variants in human ROBO1 cause distinct neurodevelopmental defects through different mechanisms.

Münch et al (2022 - PMID: 35227688) Biallelic
Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract

Woodring et al (2021 - PMID: 34193621) - Probably not relevant (VUS)
Uncertain, Not Unimportant: Callosal Dysgenesis and Variants of Uncertain Significance in ROBO1

Liu et al (2020 - PMID: 31448886) Monoallelic
A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome.

Dateki et al (2019 - PMID: 30692597) Biallelic - This individual has been incl. in the study by Munch et al
A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency

Rasmussen et al (2018 - PMID: 29194579) Biallelic
Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

Kruszka et al (2017 - PMID: 28592524) Monoallelic
Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects

Bashamboo et al (2017 - PMID: 28402530) Monoallelic
Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome

Calloni et al (2017 - PMID: 28286008) Biallelic
Compound Heterozygous Variants in ROBO1 Cause a Neurodevelopmental Disorder With Absence of Transverse Pontine Fibers and Thinning of the Anterior Commissure and Corpus Callosum
Sources: Literature
Renal tubulopathies v2.50 KCNJ16 Julia Baptista reviewed gene: KCNJ16: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811157, 33840812; Phenotypes: Renal tubulopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.62 PRDM13 Julia Baptista gene: PRDM13 was added
gene: PRDM13 was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 35390279; 34730112
Phenotypes for gene: PRDM13 were set to Cerebellar hypoplasia
Review for gene: PRDM13 was set to GREEN
Added comment: Coolen and colleagues (PMID:35390279) reported eight individuals from four families of different origins with loss-of-function PRDM13 variants. Phenotypic findings included cerebellar hypoplasia and perinatal lethality associated with severe brainstem dysfunctions (e.g., feeding and respiratory difficulties, central apnea, bradycardia).

Whittaker et al (PMID: 34730112) had previously described two families from Malta with a homozygous PRDM13 deletion and intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty
Sources: Literature
Intellectual disability v3.1568 CELF2 Julia Baptista gene: CELF2 was added
gene: CELF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 34107259; 33131106
Phenotypes for gene: CELF2 were set to Developmental delay; epileptic encephalopathy
Mode of pathogenicity for gene: CELF2 was set to Other
Review for gene: CELF2 was set to GREEN
Added comment: De novo missense variants in six individuals (PMID:34107259). The variants cluster on the C‐terminus, a nuclear localization sign. Phenotypic findings include global developmental delay with moderate to severe impairment of speech and language capacities, infantile spasms, stereotypic movements and/or aggressive behaviors, and one individual was diagnosed with ASD.

A previous publication (PMID: 33131106) reported five unrelated individuals (four de novo). Two missense variants, one frameshift predicted to escape NMD and one splice site variant, c.272‐1G>C were identified; these variants, except the splicing, clustered on the C‐terminus.
Sources: Literature
Intellectual disability v3.1568 POLR3B Arina Puzriakova Mode of inheritance for gene: POLR3B was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pulmonary fibrosis familial v0.9 CSF2RA Arina Puzriakova Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Likely inborn error of metabolism v2.253 TARS2 Arina Puzriakova Mode of inheritance for gene: TARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.244 SLITRK6 Arina Puzriakova Mode of inheritance for gene: SLITRK6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1567 HIST1H4C Arina Puzriakova Publications for gene: HIST1H4C were set to 28920961
Intellectual disability v3.1566 HIST1H4C Arina Puzriakova Phenotypes for gene: HIST1H4C were changed from Growth delay, microcephaly and intellectual disability to Tessadori-van Haaften neurodevelopmental syndrome 1, OMIM:619758
Intellectual disability v3.1565 HIST1H4C Arina Puzriakova Mode of pathogenicity for gene: HIST1H4C was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1565 HIST1H4C Arina Puzriakova Mode of inheritance for gene: HIST1H4C was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.243 CISD2 Arina Puzriakova Mode of inheritance for gene: CISD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.259 ARL13B Arina Puzriakova Mode of inheritance for gene: ARL13B was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.232 TAZ Arina Puzriakova commented on gene: TAZ
Hereditary neuropathy or pain disorder v1.101 TAZ Arina Puzriakova commented on gene: TAZ
Paediatric or syndromic cardiomyopathy v1.70 TAZ Arina Puzriakova commented on gene: TAZ
Mitochondrial disorders v2.103 TAZ Arina Puzriakova commented on gene: TAZ
Intellectual disability v3.1564 TAZ Arina Puzriakova commented on gene: TAZ
Hereditary neuropathy v1.453 TAZ Arina Puzriakova commented on gene: TAZ
DDG2P v2.72 TAZ Arina Puzriakova commented on gene: TAZ
Fetal anomalies v1.860 TAZ Arina Puzriakova commented on gene: TAZ
Possible mitochondrial disorder - nuclear genes v1.79 TAZ Arina Puzriakova commented on gene: TAZ
Likely inborn error of metabolism v2.252 TAZ Arina Puzriakova commented on gene: TAZ
Undiagnosed metabolic disorders v1.532 TAZ Arina Puzriakova commented on gene: TAZ
Cytopenia - NOT Fanconi anaemia v1.69 TAZ Arina Puzriakova commented on gene: TAZ
Cytopenias and congenital anaemias v1.106 TAZ Arina Puzriakova commented on gene: TAZ
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 TAZ Arina Puzriakova commented on gene: TAZ
Dilated Cardiomyopathy and conduction defects v1.77 TAZ Arina Puzriakova commented on gene: TAZ
COVID-19 research v1.126 TAZ Arina Puzriakova commented on gene: TAZ
Fetal hydrops v1.55 TAZ Arina Puzriakova commented on gene: TAZ
Hyperammonaemia v1.13 TAZ Arina Puzriakova commented on gene: TAZ
Childhood onset dystonia, chorea or related movement disorder v1.232 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Hereditary neuropathy or pain disorder v1.101 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Paediatric or syndromic cardiomyopathy v1.70 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Mitochondrial disorders v2.103 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Intellectual disability v3.1564 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Hereditary neuropathy v1.453 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
DDG2P v2.72 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Fetal anomalies v1.860 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Possible mitochondrial disorder - nuclear genes v1.79 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Likely inborn error of metabolism v2.252 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Undiagnosed metabolic disorders v1.532 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Cytopenia - NOT Fanconi anaemia v1.69 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Cytopenias and congenital anaemias v1.106 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Dilated Cardiomyopathy and conduction defects v1.77 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
COVID-19 research v1.126 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Fetal hydrops v1.55 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Hyperammonaemia v1.13 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Left Ventricular Noncompaction Cardiomyopathy v1.4 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Left Ventricular Noncompaction Cardiomyopathy v1.4 TAZ Arina Puzriakova commented on gene: TAZ
Sarcoma susceptibility v1.69 T Arina Puzriakova Tag new-gene-name tag was added to gene: T.
Sarcoma susceptibility v1.69 T Arina Puzriakova commented on gene: T: Added new-gene-name tag, new approved HGNC gene symbol is TBXT
DDG2P v2.72 PIH1D3 Arina Puzriakova commented on gene: PIH1D3
Fetal anomalies v1.860 PIH1D3 Arina Puzriakova commented on gene: PIH1D3: Added new-gene-name tag, new approved HGNC gene symbol for PIH1D3 is DNAAF6
Respiratory ciliopathies including non-CF bronchiectasis v1.56 PIH1D3 Arina Puzriakova commented on gene: PIH1D3
Laterality disorders and isomerism v1.47 PIH1D3 Arina Puzriakova commented on gene: PIH1D3
Primary ciliary disorders v1.40 PIH1D3 Arina Puzriakova commented on gene: PIH1D3
DDG2P v2.72 PIH1D3 Arina Puzriakova Tag new-gene-name tag was added to gene: PIH1D3.
Fetal anomalies v1.860 PIH1D3 Arina Puzriakova Tag new-gene-name tag was added to gene: PIH1D3.
Respiratory ciliopathies including non-CF bronchiectasis v1.56 PIH1D3 Arina Puzriakova Tag new-gene-name tag was added to gene: PIH1D3.
Laterality disorders and isomerism v1.47 PIH1D3 Arina Puzriakova Tag new-gene-name tag was added to gene: PIH1D3.
Primary ciliary disorders v1.40 PIH1D3 Arina Puzriakova Tag new-gene-name tag was added to gene: PIH1D3.
Hereditary neuropathy or pain disorder v1.101 MARS Arina Puzriakova commented on gene: MARS
Pulmonary fibrosis familial v0.9 MARS Arina Puzriakova commented on gene: MARS: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1
Pulmonary fibrosis familial v0.9 MARS Arina Puzriakova Tag new-gene-name tag was added to gene: MARS.
Hereditary neuropathy or pain disorder v1.101 MARS Arina Puzriakova Tag new-gene-name tag was added to gene: MARS.
Intellectual disability v3.1564 IMPAD1 Arina Puzriakova commented on gene: IMPAD1: Added new-gene-name tag, new approved HGNC gene symbol for IMPAD1 is BPNT2
Clefting v2.67 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
DDG2P v2.72 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.75 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Fetal anomalies v1.860 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Skeletal dysplasia v2.206 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Intellectual disability v3.1564 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Clefting v2.67 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
DDG2P v2.72 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.75 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Fetal anomalies v1.860 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Skeletal dysplasia v2.206 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Fetal anomalies v1.860 FAM46A Arina Puzriakova commented on gene: FAM46A: Added new-gene-name tag, new approved HGNC gene symbol is TENT5A
Fetal anomalies v1.860 FAM46A Arina Puzriakova Tag new-gene-name tag was added to gene: FAM46A.
Skeletal ciliopathies v1.17 C8orf37 Arina Puzriakova commented on gene: C8orf37
Renal ciliopathies v1.64 C8orf37 Arina Puzriakova commented on gene: C8orf37
Ophthalmological ciliopathies v1.30 C8orf37 Arina Puzriakova commented on gene: C8orf37
Rare multisystem ciliopathy disorders v1.160 C8orf37 Arina Puzriakova commented on gene: C8orf37
Structural eye disease v1.122 C8orf37 Arina Puzriakova commented on gene: C8orf37
Retinal disorders v2.258 C8orf37 Arina Puzriakova commented on gene: C8orf37
Intellectual disability v3.1564 C8orf37 Arina Puzriakova commented on gene: C8orf37
DDG2P v2.72 C8orf37 Arina Puzriakova commented on gene: C8orf37
Fetal anomalies v1.860 C8orf37 Arina Puzriakova commented on gene: C8orf37
Bardet Biedl syndrome v1.13 C8orf37 Arina Puzriakova commented on gene: C8orf37
Limb disorders v2.78 C8orf37 Arina Puzriakova commented on gene: C8orf37
Glaucoma (developmental) v1.42 C8orf37 Arina Puzriakova commented on gene: C8orf37
Skeletal ciliopathies v1.17 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Renal ciliopathies v1.64 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Ophthalmological ciliopathies v1.30 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Rare multisystem ciliopathy disorders v1.160 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Structural eye disease v1.122 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Retinal disorders v2.258 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Intellectual disability v3.1564 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
DDG2P v2.72 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Fetal anomalies v1.860 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Bardet Biedl syndrome v1.13 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Limb disorders v2.78 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Glaucoma (developmental) v1.42 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Distal myopathies v1.47 ADSSL1 Arina Puzriakova commented on gene: ADSSL1
Congenital myopathy v2.83 ADSSL1 Arina Puzriakova commented on gene: ADSSL1
Congenital myopathy v2.83 ADSSL1 Arina Puzriakova Tag new-gene-name tag was added to gene: ADSSL1.
Distal myopathies v1.47 ADSSL1 Arina Puzriakova Tag new-gene-name tag was added to gene: ADSSL1.
Cholestasis v1.107 ZFYVE19 Arina Puzriakova Tag gene-checked tag was added to gene: ZFYVE19.
Childhood onset dystonia, chorea or related movement disorder v1.232 YIF1B Arina Puzriakova Tag gene-checked tag was added to gene: YIF1B.
Intellectual disability v3.1564 YIF1B Arina Puzriakova Tag gene-checked tag was added to gene: YIF1B.
Fetal anomalies v1.860 WBP11 Arina Puzriakova Tag gene-checked tag was added to gene: WBP11.
Paediatric disorders - additional genes v1.96 WBP11 Arina Puzriakova Tag gene-checked tag was added to gene: WBP11.
Skeletal dysplasia v2.206 WBP11 Arina Puzriakova Tag gene-checked tag was added to gene: WBP11.
Retinal disorders v2.258 USP45 Arina Puzriakova Tag gene-checked tag was added to gene: USP45.
Severe microcephaly v2.300 TUBGCP2 Arina Puzriakova Tag gene-checked tag was added to gene: TUBGCP2.
Malformations of cortical development v2.141 TUBGCP2 Arina Puzriakova Tag gene-checked tag was added to gene: TUBGCP2.
Intellectual disability v3.1564 TTC5 Arina Puzriakova Tag gene-checked tag was added to gene: TTC5.
Severe microcephaly v2.300 TTC5 Arina Puzriakova Tag gene-checked tag was added to gene: TTC5.
Hydrocephalus v2.129 TRIM71 Arina Puzriakova Tag gene-checked tag was added to gene: TRIM71.
Intellectual disability v3.1564 RFX7 Arina Puzriakova Tag gene-checked tag was added to gene: RFX7.
Intellectual disability v3.1564 RFX4 Arina Puzriakova Tag gene-checked tag was added to gene: RFX4.
Intellectual disability v3.1564 RFX3 Arina Puzriakova Tag gene-checked tag was added to gene: RFX3.
Intellectual disability v3.1564 PTRHD1 Arina Puzriakova Tag gene-checked tag was added to gene: PTRHD1.
Intellectual disability v3.1564 PTPN4 Arina Puzriakova Tag gene-checked tag was added to gene: PTPN4.
Bleeding and platelet disorders v1.40 PTGS1 Arina Puzriakova Tag gene-checked tag was added to gene: PTGS1.
Fetal anomalies v1.860 PRIM1 Arina Puzriakova Tag gene-checked tag was added to gene: PRIM1.
Severe microcephaly v2.300 PRIM1 Arina Puzriakova Tag gene-checked tag was added to gene: PRIM1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 PRIM1 Arina Puzriakova Tag gene-checked tag was added to gene: PRIM1.
Intellectual disability v3.1564 PRICKLE2 Arina Puzriakova Tag gene-checked tag was added to gene: PRICKLE2.
Intellectual disability v3.1564 PGM2L1 Arina Puzriakova Tag gene-checked tag was added to gene: PGM2L1.
Early onset or syndromic epilepsy v2.519 PGM2L1 Arina Puzriakova Tag gene-checked tag was added to gene: PGM2L1.
Severe early-onset obesity v2.49 PGM2L1 Arina Puzriakova Tag gene-checked tag was added to gene: PGM2L1.
Severe microcephaly v2.300 PCDHGC4 Arina Puzriakova Tag gene-checked tag was added to gene: PCDHGC4.
Early onset or syndromic epilepsy v2.519 PCDHGC4 Arina Puzriakova Tag gene-checked tag was added to gene: PCDHGC4.
Intellectual disability v3.1564 PCDHGC4 Arina Puzriakova Tag gene-checked tag was added to gene: PCDHGC4.
Multi locus imprinting disorders v0.14 NLRP5 Arina Puzriakova Tag gene-checked tag was added to gene: NLRP5.
Multi locus imprinting disorders v0.14 NLRP2 Arina Puzriakova Tag gene-checked tag was added to gene: NLRP2.
Familial diabetes v1.66 NKX2-2 Arina Puzriakova Tag gene-checked tag was added to gene: NKX2-2.
Neonatal diabetes v2.38 NKX2-2 Arina Puzriakova Tag gene-checked tag was added to gene: NKX2-2.
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.66 NKX2-2 Arina Puzriakova Tag gene-checked tag was added to gene: NKX2-2.
Acute rhabdomyolysis v0.10 OBSCN Arina Puzriakova Tag gene-checked tag was added to gene: OBSCN.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 OAS1 Arina Puzriakova Tag gene-checked tag was added to gene: OAS1.
Paediatric or syndromic cardiomyopathy v1.70 NRAP Arina Puzriakova Tag gene-checked tag was added to gene: NRAP.
Dilated and arrhythmogenic cardiomyopathy v1.26 NRAP Arina Puzriakova Tag gene-checked tag was added to gene: NRAP.
Intellectual disability v3.1564 NR4A2 Arina Puzriakova Tag gene-checked tag was added to gene: NR4A2.
Early onset or syndromic epilepsy v2.519 NR4A2 Arina Puzriakova Tag gene-checked tag was added to gene: NR4A2.
Intellectual disability v3.1564 NCKAP1 Arina Puzriakova Tag gene-checked tag was added to gene: NCKAP1.
Fetal anomalies v1.860 MYT1 Arina Puzriakova Tag gene-checked tag was added to gene: MYT1.
Paediatric or syndromic cardiomyopathy v1.70 MYLK3 Arina Puzriakova Tag gene-checked tag was added to gene: MYLK3.
Dilated and arrhythmogenic cardiomyopathy v1.26 MYLK3 Arina Puzriakova Tag gene-checked tag was added to gene: MYLK3.
Fetal anomalies v1.860 MYH10 Arina Puzriakova Tag gene-checked tag was added to gene: MYH10.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 ZNF341 Arina Puzriakova Tag gene-checked tag was added to gene: ZNF341.
Early onset or syndromic epilepsy v2.519 ADD1 Konstantinos Varvagiannis gene: ADD1 was added
gene: ADD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Global developmental delay; Intellectual disability; Seizures; Ventriculomegaly; Abnormality of the corpus callosum
Penetrance for gene: ADD1 were set to unknown
Review for gene: ADD1 was set to AMBER
Added comment: A recent study suggests an ADD1-related phenotype (3 subjects with monoallelic de novo variants/1 with biallelic variants) with DD/ID and ventriculomegaly or corpus callosum dysgenesis and possibly seizures among the features.

There is currently no associated phenotype in other databases (OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the current panel with amber / green rating (3 subjects/variants/families, role of the gene and mouse models recapitulating ventriculomegaly/CC abnormalities, relevant expression, variant studies demonstrating abn. protein levels and/or disruption of adducin heterodimer formation || monoallelic vs bi-allelic variants).

Please consider inclusion in other possibly relevant gene panels (e.g. for corpus callosum / ventriculomegaly) [ Not added ].

--------

Qi et al (2022 - PMID: 34906466) describe the phenotype of 3 unrelated individuals with monoallelic de novo ADD1 pathogenic variants as well as of a fourth homozygous for a missense SNV.

Overall, the authors propose a common phenotype consisting of morphological brain abnormalities (incl. ventriculomegaly and corpus callosum dysgenesis) and neurological symptoms such as DD and/or ID and attention deficit.

All individuals were investigated with singleton/trio ES.

De novo variants - phenotype:
One individual investigated for hypotonia, DD & ID, partial ACC, well controlled seizures (on ketogenic diet) and proportional short stature harbored a de novo stopgain variant (NM_014189.3:c.1418G>A / p.Trp473*) absent from gnomAD.
Another affected subject with hypotonia, FTT/feeding difficulties, mild motor delays complete ACC, a seizure (2y11m), staring spells without EEG correlate, and fatigue (with low coenz. Q10, and complex I & IV deficiency in muscle biopsy) had a de novo fs variant (NM_001119:c.2029_2039del / p.Glu680Argfs*7 - gnomAD:0) and a VUS in a gene not associated with phenotype to date.
A 3rd subject investigated for seizures (onset:1y), speech delay, mild ID, ADHD, without MRI abnormalities harbored a de novo missense SNV (NM_001119:c.670C>T / p.His224Tyr - gnomAD:0) and with cmp htz for 2 missense SPTBN2 SNV not fitting the phenotype (no ataxia).

Biallelic variants - phenotype:
One individual with ID, and ACC, abnormal sulcation, enlarged lateral and 3rd ventricles, abnormal of white matter and hypoplastic vermis upon MRI was reported to harbor in homozygosity a missense SNV (NM_001119:c.169A>T / p.Arg57Trp). There was an additional variant in a gene without associated phenotype to date and not expressed in brain.

Role of the encoded protein:
ADD1 encodes adducin 1/alpha (similar to ADD2, ADD3 encoding other adducins). As the authors note, adducins are cytoskeleton proteins critical for osmotic rigidity and cell shape. In neurons they have been reported to form membrane associated periodic ring-like structures with actin and β-spectrin. Deletion of Add1 in mice results in increased MPS ring diameter and axonal degeneration (several refs provided).

ADD1/2/3 form heterodimers which in turn form heterotetramers. ADD1 is expressed in most tissues.

Mouse model:
Previous mouse models have demonstrated that Add1 null mice have also undetectable ADD2/3 (suggesting a role for stabilization of the latter) and exhibit growth delay, anemia and develop lethal hydrocephalus and ventriculomegaly with 50% penetrance (cited PMIDs: 27068466, 18723693). Here the authors demonstrated that surviving mice had ventriculomegaly and thinning of corpus callosum thus recapitulating the respective human phenotypes. Htz mice also presented thinner CC, though not to a statistically significant extent.

ADD1 expression and isoforms:
- Performing mRNA studies and W.Blot in (developing - GW15-17) human or mouse brain (E12.5-P40) the authors demonstrated dynamic expression of ADD1 with differentially expressed isoforms, notably alternative splicing of ex10 and ex15 with NM_176801 (extended ex10, inclusion of ex15) corresponding to a neuronal isoform and NM_001119 (shorter ex10, exclusion of ex15) corresponding to a neural progenitor cell (NPC) isoform.
- Variants here reported appear to affect both isoforms with the exception of NM_001119:c.2029_2039del / p.Glu680Argfs*7 affecting only the longer NPC one.
- PTBP1 is an RNA binding protein expressed in NPCs known to suppress neuronal exon insertion. The authors demonstrated in mouse Neuro2A cells, through shRNA targeting of Ptbp1, that the latter suppresses the neuronal Add1 isoform.

Variant studies demonstrated that effect of variants was mediated by decreased protein levels and/or disruption of adducin complex formation (ADD1-ADD2 dimer formation known to be mediated by N- and C- terminal ADD1 domains):
- Expression of Arg57Trp (found in hmz in one individual) NPC and neuronal isoforms in Neuro2a cells showed that while protein levels were not significantly affected, there were (also) truncated protein products for both isoforms suggesting that aberrant splicing or protein translation/cleavage may apply.
- The authors generated HEK293FT cells for the truncating variants demonstrating decreased protein levels (using N-/C- terminal antibodies).
- Reduced (HA-tagged)-ADD1-(V5-tagged)-ADD2 protein interaction was shown to apply for the Arg57Trp and Arg473* in HEK293FT cells. Similarly in Neuro2a cells, reduced ADD1-ADD2 interaction was shown for His224Tyr.
Sources: Literature
Intellectual disability v3.1564 ADD1 Konstantinos Varvagiannis gene: ADD1 was added
gene: ADD1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Global developmental delay; Intellectual disability; Seizures; Ventriculomegaly; Abnormality of the corpus callosum
Penetrance for gene: ADD1 were set to unknown
Review for gene: ADD1 was set to AMBER
Added comment: A recent study suggests an ADD1-related phenotype (3 subjects with monoallelic de novo variants/1 with biallelic variants) with DD/ID and ventriculomegaly or corpus callosum dysgenesis and possibly seizures among the features.

There is currently no associated phenotype in other databases (OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the current panel with amber / green rating (3 subjects/variants/families, role of the gene and mouse models recapitulating ventriculomegaly/CC abnormalities, relevant expression, variant studies demonstrating abn. protein levels and/or disruption of adducin heterodimer formation || monoallelic vs bi-allelic variants).

Please consider inclusion in other possibly relevant gene panels (e.g. for corpus callosum / ventriculomegaly) [ Not added ].

--------

Qi et al (2022 - PMID: 34906466) describe the phenotype of 3 unrelated individuals with monoallelic de novo ADD1 pathogenic variants as well as of a fourth homozygous for a missense SNV.

Overall, the authors propose a common phenotype consisting of morphological brain abnormalities (incl. ventriculomegaly and corpus callosum dysgenesis) and neurological symptoms such as DD and/or ID and attention deficit.

All individuals were investigated with singleton/trio ES.

De novo variants - phenotype:
One individual investigated for hypotonia, DD & ID, partial ACC, well controlled seizures (on ketogenic diet) and proportional short stature harbored a de novo stopgain variant (NM_014189.3:c.1418G>A / p.Trp473*) absent from gnomAD.
Another affected subject with hypotonia, FTT/feeding difficulties, mild motor delays complete ACC, a seizure (2y11m), staring spells without EEG correlate, and fatigue (with low coenz. Q10, and complex I & IV deficiency in muscle biopsy) had a de novo fs variant (NM_001119:c.2029_2039del / p.Glu680Argfs*7 - gnomAD:0) and a VUS in a gene not associated with phenotype to date.
A 3rd subject investigated for seizures (onset:1y), speech delay, mild ID, ADHD, without MRI abnormalities harbored a de novo missense SNV (NM_001119:c.670C>T / p.His224Tyr - gnomAD:0) and with cmp htz for 2 missense SPTBN2 SNV not fitting the phenotype (no ataxia).

Biallelic variants - phenotype:
One individual with ID, and ACC, abnormal sulcation, enlarged lateral and 3rd ventricles, abnormal of white matter and hypoplastic vermis upon MRI was reported to harbor in homozygosity a missense SNV (NM_001119:c.169A>T / p.Arg57Trp). There was an additional variant in a gene without associated phenotype to date and not expressed in brain.

Role of the encoded protein:
ADD1 encodes adducin 1/alpha (similar to ADD2, ADD3 encoding other adducins). As the authors note, adducins are cytoskeleton proteins critical for osmotic rigidity and cell shape. In neurons they have been reported to form membrane associated periodic ring-like structures with actin and β-spectrin. Deletion of Add1 in mice results in increased MPS ring diameter and axonal degeneration (several refs provided).

ADD1/2/3 form heterodimers which in turn form heterotetramers. ADD1 is expressed in most tissues.

Mouse model:
Previous mouse models have demonstrated that Add1 null mice have also undetectable ADD2/3 (suggesting a role for stabilization of the latter) and exhibit growth delay, anemia and develop lethal hydrocephalus and ventriculomegaly with 50% penetrance (cited PMIDs: 27068466, 18723693). Here the authors demonstrated that surviving mice had ventriculomegaly and thinning of corpus callosum thus recapitulating the respective human phenotypes. Htz mice also presented thinner CC, though not to a statistically significant extent.

ADD1 expression and isoforms:
- Performing mRNA studies and W.Blot in (developing - GW15-17) human or mouse brain (E12.5-P40) the authors demonstrated dynamic expression of ADD1 with differentially expressed isoforms, notably alternative splicing of ex10 and ex15 with NM_176801 (extended ex10, inclusion of ex15) corresponding to a neuronal isoform and NM_001119 (shorter ex10, exclusion of ex15) corresponding to a neural progenitor cell (NPC) isoform.
- Variants here reported appear to affect both isoforms with the exception of NM_001119:c.2029_2039del / p.Glu680Argfs*7 affecting only the longer NPC one.
- PTBP1 is an RNA binding protein expressed in NPCs known to suppress neuronal exon insertion. The authors demonstrated in mouse Neuro2A cells, through shRNA targeting of Ptbp1, that the latter suppresses the neuronal Add1 isoform.

Variant studies demonstrated that effect of variants was mediated by decreased protein levels and/or disruption of adducin complex formation (ADD1-ADD2 dimer formation known to be mediated by N- and C- terminal ADD1 domains):
- Expression of Arg57Trp (found in hmz in one individual) NPC and neuronal isoforms in Neuro2a cells showed that while protein levels were not significantly affected, there were (also) truncated protein products for both isoforms suggesting that aberrant splicing or protein translation/cleavage may apply.
- The authors generated HEK293FT cells for the truncating variants demonstrating decreased protein levels (using N-/C- terminal antibodies).
- Reduced (HA-tagged)-ADD1-(V5-tagged)-ADD2 protein interaction was shown to apply for the Arg57Trp and Arg473* in HEK293FT cells. Similarly in Neuro2a cells, reduced ADD1-ADD2 interaction was shown for His224Tyr.
Sources: Literature
Mitochondrial disorders v2.103 MT-TR Eleanor Williams Tag gene-checked tag was added to gene: MT-TR.
Likely inborn error of metabolism v2.252 MT-TR Eleanor Williams Tag gene-checked tag was added to gene: MT-TR.
Undiagnosed metabolic disorders v1.532 MT-TR Eleanor Williams Tag gene-checked tag was added to gene: MT-TR.
Mitochondrial disorders v2.103 MT-ND5 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND5.
Undiagnosed metabolic disorders v1.532 MT-ND5 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND5.
Mitochondrial disorders v2.103 MT-ND4L Eleanor Williams Tag gene-checked tag was added to gene: MT-ND4L.
Undiagnosed metabolic disorders v1.532 MT-ND4L Eleanor Williams Tag gene-checked tag was added to gene: MT-ND4L.
Mitochondrial disorders v2.103 MT-ND4 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND4.
Undiagnosed metabolic disorders v1.532 MT-ND4 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND4.
Optic neuropathy v2.68 MT-ND4 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND4.
Mitochondrial disorders v2.103 MT-ND3 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND3.
Undiagnosed metabolic disorders v1.532 MT-ND3 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND3.
Mitochondrial disorders v2.103 MT-ND2 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND2.
Undiagnosed metabolic disorders v1.532 MT-ND2 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND2.
Sarcoma susceptibility v1.69 FANCC Dmitrijs Rots gene: FANCC was added
gene: FANCC was added to Sarcoma susceptibility. Sources: Literature
Mode of inheritance for gene: FANCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FANCC were set to PMID: 35512711
Phenotypes for gene: FANCC were set to Ewing Sarcome
Penetrance for gene: FANCC were set to unknown
Review for gene: FANCC was set to GREEN
Added comment: At least 6 individuals in PMID: 35512711 with significant enrichment (OR=12 and 7 in discovery and validation cohorts, respectively)
Sources: Literature
Early onset or syndromic epilepsy v2.519 CELF2 Julia Baptista reviewed gene: CELF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34107259, 33131106; Phenotypes: Developmental delay, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1564 THUMPD1 Julia Baptista reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35196516; Phenotypes: Intellectual disability, Microcephaly, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.116 ZBTB7A Julia Baptista gene: ZBTB7A was added
gene: ZBTB7A was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders. Sources: Literature
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB7A were set to 34515416
Phenotypes for gene: ZBTB7A were set to intellectual disability; macrocephaly; overgrowth
Review for gene: ZBTB7A was set to GREEN
gene: ZBTB7A was marked as current diagnostic
Added comment: Syndromic mild ID reported in 12 individuals from 10 families. Additional clinical features included macrocephaly, and overgrowth of adenoid tissue.
De novo variants confirmed in eight families.
Frameshift, nonsense and missense variants identified throughout the gene.
Sources: Literature
Intellectual disability v3.1564 ZBTB7A Julia Baptista reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34515416; Phenotypes: intellectual disability, macrocephaly, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Paediatric or syndromic cardiomyopathy v1.70 LMOD2 Julia Baptista gene: LMOD2 was added
gene: LMOD2 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: LMOD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMOD2 were set to PMID: 35082396; 35188328; 34888509; 31517052
Phenotypes for gene: LMOD2 were set to dilated cardiomyopathy
Review for gene: LMOD2 was set to GREEN
Added comment: Biallelic loss of function variants reported in four families to date. Three with homozygous variants and one compound heterozygous. Frameshift, canonical splice site and nonsense variants reported. Null mice model recapitulates the human phenotype of severe neonatal-onset cardiomyopathy.
Sources: Literature
Mitochondrial disorders v2.103 MT-ND1 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND1.
Undiagnosed metabolic disorders v1.532 MT-ND1 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND1.
Optic neuropathy v2.68 MT-ND1 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND1.
Structural basal ganglia disorders v1.32 MT-ND1 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND1.
Mitochondrial disorders v2.103 MT-TS1 Eleanor Williams Tag gene-checked tag was added to gene: MT-TS1.
Monogenic hearing loss v2.242 MT-TS1 Eleanor Williams Tag gene-checked tag was added to gene: MT-TS1.
Likely inborn error of metabolism v2.252 MT-TS1 Eleanor Williams Tag gene-checked tag was added to gene: MT-TS1.
Mitochondrial disorders v2.103 MT-TS2 Eleanor Williams Tag gene-checked tag was added to gene: MT-TS2.
Likely inborn error of metabolism v2.252 MT-TS2 Eleanor Williams Tag gene-checked tag was added to gene: MT-TS2.
Mitochondrial disorders v2.103 MT-TV Eleanor Williams Tag gene-checked tag was added to gene: MT-TV.
Likely inborn error of metabolism v2.252 MT-TV Eleanor Williams Tag gene-checked tag was added to gene: MT-TV.
Rare anaemia v1.40 RPL9 Eleanor Williams Tag gene-checked tag was added to gene: RPL9.
Haematological malignancies cancer susceptibility v2.30 RPS15 Eleanor Williams Tag gene-checked tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.30 RPS15 Eleanor Williams commented on gene: RPS15
Haematological malignancies for rare disease v1.12 RPS15 Eleanor Williams Tag gene-checked tag was added to gene: RPS15.
Haematological malignancies for rare disease v1.12 RPS15 Eleanor Williams commented on gene: RPS15
Haematological malignancies cancer susceptibility v2.30 RPS27A Eleanor Williams Tag gene-checked tag was added to gene: RPS27A.
Haematological malignancies for rare disease v1.12 RPS27A Eleanor Williams Tag gene-checked tag was added to gene: RPS27A.
Congenital myopathy v2.83 RYR3 Eleanor Williams Tag gene-checked tag was added to gene: RYR3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 SASH3 Eleanor Williams Tag gene-checked tag was added to gene: SASH3.
Early onset or syndromic epilepsy v2.519 SCAF4 Eleanor Williams Tag gene-checked tag was added to gene: SCAF4.
White matter disorders and cerebral calcification - narrow panel v1.236 SCAF4 Eleanor Williams Tag gene-checked tag was added to gene: SCAF4.
DDG2P v2.72 SIM1 Eleanor Williams Tag gene-checked tag was added to gene: SIM1.
Severe early-onset obesity v2.49 SIM1 Eleanor Williams Tag gene-checked tag was added to gene: SIM1.
Neurological ciliopathies v1.31 SCLT1 Eleanor Williams Tag gene-checked tag was added to gene: SCLT1.
Ophthalmological ciliopathies v1.30 SCLT1 Eleanor Williams Tag gene-checked tag was added to gene: SCLT1.
Rare multisystem ciliopathy disorders v1.160 SCLT1 Eleanor Williams Tag gene-checked tag was added to gene: SCLT1.
Fetal anomalies v1.860 SCLT1 Eleanor Williams Tag gene-checked tag was added to gene: SCLT1.
Rare anaemia v1.40 RPL31 Eleanor Williams Tag gene-checked tag was added to gene: RPL31.
Haematological malignancies cancer susceptibility v2.30 RPL31 Eleanor Williams Tag gene-checked tag was added to gene: RPL31.
Haematological malignancies for rare disease v1.12 RPL31 Eleanor Williams Tag gene-checked tag was added to gene: RPL31.
Haematological malignancies cancer susceptibility v2.30 RPL23 Eleanor Williams Tag gene-checked tag was added to gene: RPL23.
Haematological malignancies for rare disease v1.12 RPL23 Eleanor Williams Tag gene-checked tag was added to gene: RPL23.
Fetal anomalies v1.860 ROBO1 Eleanor Williams Tag gene-checked tag was added to gene: ROBO1.
Paediatric or syndromic cardiomyopathy v1.70 PPP1R13L Eleanor Williams Tag gene-checked tag was added to gene: PPP1R13L.
Proteinuric renal disease v2.75 PODXL Eleanor Williams Tag gene-checked tag was added to gene: PODXL.
Unexplained young onset end-stage renal disease v1.36 PODXL Eleanor Williams Tag gene-checked tag was added to gene: PODXL.
Intellectual disability v3.1564 SIN3B Eleanor Williams Tag gene-checked tag was added to gene: SIN3B.
Mitochondrial disorders v2.103 SLC25A32 Eleanor Williams Tag gene-checked tag was added to gene: SLC25A32.
Possible mitochondrial disorder - nuclear genes v1.79 SLC25A32 Eleanor Williams Tag gene-checked tag was added to gene: SLC25A32.
Likely inborn error of metabolism v2.252 SLC25A32 Eleanor Williams Tag gene-checked tag was added to gene: SLC25A32.
Congenital hypothyroidism v2.11 SLC26A7 Eleanor Williams Tag gene-checked tag was added to gene: SLC26A7.
Intellectual disability v3.1564 SMARCA5 Eleanor Williams Tag gene-checked tag was added to gene: SMARCA5.
Severe microcephaly v2.300 SMARCA5 Eleanor Williams Tag gene-checked tag was added to gene: SMARCA5.
Fetal anomalies v1.860 SMARCC1 Eleanor Williams Tag gene-checked tag was added to gene: SMARCC1.
Hydrocephalus v2.129 SMARCC1 Eleanor Williams Tag gene-checked tag was added to gene: SMARCC1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 SNORA31 Eleanor Williams Tag gene-checked tag was added to gene: SNORA31.
Intellectual disability v3.1564 SNX27 Eleanor Williams Tag gene-checked tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.519 SNX27 Eleanor Williams Tag gene-checked tag was added to gene: SNX27.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 STXBP3 Eleanor Williams Tag gene-checked tag was added to gene: STXBP3.
Intellectual disability v3.1564 SVBP Eleanor Williams Tag gene-checked tag was added to gene: SVBP.
Severe microcephaly v2.300 SVBP Eleanor Williams Tag gene-checked tag was added to gene: SVBP.
Intellectual disability v3.1564 SYNCRIP Eleanor Williams Tag gene-checked tag was added to gene: SYNCRIP.
Early onset or syndromic epilepsy v2.519 SYNCRIP Eleanor Williams Tag gene-checked tag was added to gene: SYNCRIP.
Intellectual disability v3.1564 TBC1D2B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.519 TBC1D2B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D2B.
Ophthalmological ciliopathies v1.30 TBC1D32 Eleanor Williams Tag gene-checked tag was added to gene: TBC1D32.
Rare multisystem ciliopathy disorders v1.160 TBC1D32 Eleanor Williams Tag gene-checked tag was added to gene: TBC1D32.
Fetal anomalies v1.860 TBC1D32 Eleanor Williams Tag gene-checked tag was added to gene: TBC1D32.
Malformations of cortical development v2.141 TBC1D32 Eleanor Williams Tag gene-checked tag was added to gene: TBC1D32.
Hydrocephalus v2.129 TBC1D32 Eleanor Williams Tag gene-checked tag was added to gene: TBC1D32.
Proteinuric renal disease v2.75 TBC1D8B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D8B.
Unexplained young onset end-stage renal disease v1.36 TBC1D8B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D8B.
Neurological ciliopathies v1.31 TMEM218 Eleanor Williams Tag gene-checked tag was added to gene: TMEM218.
Ophthalmological ciliopathies v1.30 TMEM218 Eleanor Williams Tag gene-checked tag was added to gene: TMEM218.
Rare multisystem ciliopathy disorders v1.160 TMEM218 Eleanor Williams Tag gene-checked tag was added to gene: TMEM218.
Retinal disorders v2.258 TMEM218 Eleanor Williams Tag gene-checked tag was added to gene: TMEM218.
Early onset or syndromic epilepsy v2.519 TMEM222 Eleanor Williams Tag gene-checked tag was added to gene: TMEM222.
Intellectual disability v3.1564 TMEM222 Eleanor Williams Tag gene-checked tag was added to gene: TMEM222.
Intellectual disability v3.1564 TMEM94 Eleanor Williams Tag gene-checked tag was added to gene: TMEM94.
Fetal anomalies v1.860 TMEM94 Eleanor Williams Tag gene-checked tag was added to gene: TMEM94.
Proteinuric renal disease v2.75 TNS2 Eleanor Williams Tag gene-checked tag was added to gene: TNS2.
Unexplained young onset end-stage renal disease v1.36 TNS2 Eleanor Williams Tag gene-checked tag was added to gene: TNS2.
Bleeding and platelet disorders v1.40 TPM4 Eleanor Williams Tag gene-checked tag was added to gene: TPM4.
Childhood onset dystonia, chorea or related movement disorder v1.232 CAMK4 Eleanor Williams Tag gene-checked tag was added to gene: CAMK4.
Intellectual disability v3.1564 CAMK4 Eleanor Williams Tag gene-checked tag was added to gene: CAMK4.
Early onset or syndromic epilepsy v2.519 CACNA1I Eleanor Williams Tag gene-checked tag was added to gene: CACNA1I.
Intellectual disability v3.1564 CACNA1I Eleanor Williams Tag gene-checked tag was added to gene: CACNA1I.
Ectodermal dysplasia v1.41 C3orf52 Eleanor Williams Tag gene-checked tag was added to gene: C3orf52.
Intellectual disability v3.1564 ATP9A Eleanor Williams Tag gene-checked tag was added to gene: ATP9A.
Intellectual disability v3.1564 ARFGEF1 Eleanor Williams Tag gene-checked tag was added to gene: ARFGEF1.
Early onset or syndromic epilepsy v2.519 ARFGEF1 Eleanor Williams Tag gene-checked tag was added to gene: ARFGEF1.
Paediatric disorders - additional genes v1.96 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
Fetal anomalies v1.860 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
Undiagnosed metabolic disorders v1.532 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
Unexplained young onset end-stage renal disease v1.36 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
CAKUT v1.167 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
Unexplained kidney failure in young people v1.113 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
VACTERL-like phenotypes v1.32 TRAP1 Eleanor Williams Tag gene-checked tag was added to gene: TRAP1.
Mitochondrial disorders v2.103 MT-TW Eleanor Williams Tag gene-checked tag was added to gene: MT-TW.
Likely inborn error of metabolism v2.252 MT-TW Eleanor Williams Tag gene-checked tag was added to gene: MT-TW.
Undiagnosed metabolic disorders v1.532 MT-TW Eleanor Williams Tag gene-checked tag was added to gene: MT-TW.
Mitochondrial disorders v2.103 MT-TQ Eleanor Williams Tag gene-checked tag was added to gene: MT-TQ.
Likely inborn error of metabolism v2.252 MT-TQ Eleanor Williams Tag gene-checked tag was added to gene: MT-TQ.
Undiagnosed metabolic disorders v1.532 MT-TQ Eleanor Williams Tag gene-checked tag was added to gene: MT-TQ.
Mitochondrial disorders v2.103 MT-CYB Eleanor Williams Tag gene-checked tag was added to gene: MT-CYB.
Likely inborn error of metabolism v2.252 MT-CYB Eleanor Williams Tag gene-checked tag was added to gene: MT-CYB.
Undiagnosed metabolic disorders v1.532 MT-CYB Eleanor Williams Tag gene-checked tag was added to gene: MT-CYB.
Mitochondrial disorders v2.103 MT-CO3 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO3.
Likely inborn error of metabolism v2.252 MT-CO3 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO3.
Undiagnosed metabolic disorders v1.532 MT-CO3 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO3.
Acute rhabdomyolysis v0.10 MT-CO2 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO2.
Mitochondrial disorders v2.103 MT-CO2 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO2.
Likely inborn error of metabolism v2.252 MT-CO2 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO2.
Undiagnosed metabolic disorders v1.532 MT-CO2 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO2.
Acute rhabdomyolysis v0.10 MT-CO1 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO1.
Mitochondrial disorders v2.103 MT-CO1 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO1.
Likely inborn error of metabolism v2.252 MT-CO1 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO1.
Undiagnosed metabolic disorders v1.532 MT-CO1 Eleanor Williams Tag gene-checked tag was added to gene: MT-CO1.
Haematological malignancies cancer susceptibility v2.30 RPL36 Eleanor Williams Tag gene-checked tag was added to gene: RPL36.
Haematological malignancies for rare disease v1.12 RPL36 Eleanor Williams Tag gene-checked tag was added to gene: RPL36.
Childhood onset dystonia, chorea or related movement disorder v1.232 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
Intellectual disability v3.1564 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
Childhood onset hereditary spastic paraplegia v2.137 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
White matter disorders and cerebral calcification - narrow panel v1.236 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
Intellectual disability v3.1564 PPP1R21 Eleanor Williams Tag gene-checked tag was added to gene: PPP1R21.
Intellectual disability v3.1564 PITRM1 Eleanor Williams Tag gene-checked tag was added to gene: PITRM1.
Intellectual disability v3.1564 NTNG2 Eleanor Williams Tag gene-checked tag was added to gene: NTNG2.
Paediatric disorders - additional genes v1.96 NHLRC2 Eleanor Williams Tag Q2_22_expert_review tag was added to gene: NHLRC2.
Paediatric disorders - additional genes v1.96 NHLRC2 Eleanor Williams Tag Q2_22_rating tag was added to gene: NHLRC2.
Tag gene-checked tag was added to gene: NHLRC2.
Rare anaemia v1.40 NHLRC2 Eleanor Williams Tag gene-checked tag was added to gene: NHLRC2.
Mitochondrial disorders v2.103 MT-TY Eleanor Williams Tag gene-checked tag was added to gene: MT-TY.
Likely inborn error of metabolism v2.252 MT-TY Eleanor Williams Tag gene-checked tag was added to gene: MT-TY.
Undiagnosed metabolic disorders v1.532 MT-TY Eleanor Williams Tag gene-checked tag was added to gene: MT-TY.
Mitochondrial disorders v2.103 MT-ATP8 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP8.
Likely inborn error of metabolism v2.252 MT-ATP8 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP8.
Undiagnosed metabolic disorders v1.532 MT-ATP8 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP8.
Skeletal muscle channelopathy v1.39 MT-ATP8 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP8.
Skeletal Muscle Channelopathies v1.45 MT-ATP8 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP8.
Hereditary neuropathy or pain disorder v1.101 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Hereditary ataxia with onset in adulthood v2.158 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Mitochondrial disorders v2.103 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Hereditary neuropathy v1.453 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Likely inborn error of metabolism v2.252 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Undiagnosed metabolic disorders v1.532 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Skeletal muscle channelopathy v1.39 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Optic neuropathy v2.68 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Structural basal ganglia disorders v1.32 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Hereditary ataxia v1.302 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Ataxia and cerebellar anomalies - narrow panel v2.295 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Skeletal Muscle Channelopathies v1.45 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Intellectual disability v3.1564 BUB1 Konstantinos Varvagiannis gene: BUB1 was added
gene: BUB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816
Phenotypes for gene: BUB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay
Penetrance for gene: BUB1 were set to Complete
Review for gene: BUB1 was set to AMBER
Added comment: A recent study provides evidence that this gene (biallelic variants) is relevant for inclusion in the DD/ID panel likely with amber / green rating (2 unrelated individuals with similar phenotype, 3 variants, role of this gene, extensive variant studies and demonstrated effects on cohesion and chromosome segregation, similarities with other disorders caused by mutations in mitosis-associated genes at the clinical and cellular level || number of affected subjects/families, different protein levels/kinase activity likely underlying few differences observed, role of monoallelic variants unclear).

This gene could probably be included in other panels e.g. for microcephaly (not added).

There is no BUB1-related phenotype in OMIM, G2P, SysID, PanelApp Australia.

------

Carvalhal, Bader et al (2022 - PMID: 35044816) describe the phenotype of 2 unrelated individuals with biallelic BUB1 pathogenic variants and provide evidence for the underlying mechanism for this condition.

Common features comprised congenital microcephaly (2/2 | -2,8 and -2.9 SDs respectively / -7 and -4,9 SDs on last evaluation), DD/ID (2/2 - in one case with formal evaluation mild), some degree of growth retardation (2/2) and cardiovascular findings (2/2 - small ASD type II). Other findings limited to one subject included Pierre-Robin sequence, Axenfeld-Rieger anomaly, choanal stenosis, hypospadias, tracheal stenosis, etc.

Initial genetic testing was normal (incl. CMA in both, metabolic testing and individual genes incl. PITX2, GREM1, FOXD3, FOXC1 for one proband).

Exome sequencing revealed homozygosity for a start-lost variant (NM_004336.4:c.2T>G / p.?) in the first subject (P1). The variant lied within a 14-Mb region of homozygosity (no reported consanguinity). The second individual (P2) was compound htz for a splice-site and a frameshift variant (c.2625+1G>A and c.2197dupG) with Sanger sequencing used for confirmation and segregation studies.

BUB1 encodes BUB1 Mitotic checkpoint serine/threonine kinase (/Budding uninhibited by benzimidazoles 1, s. cerevisiae, homolog of) a multifunctional component of the segregation machinery contributing to multiple mitotic processes. The protein has a kinetochore localization domain, multiple binding motifs and a C-terminal kinase domain (aa 784-1085) this structure allowing both kinase dependent/independent activities.

cDNA sequencing revealed that the splice variant leads to skipping of ex21 and in-frame deletion of 54 residues in the kinase domain (c.2625+1G>A / p.Val822_Leu875del).

Both individuals exhibited normal BUB1 mRNA levels (fibroblasts in both, tracheal tissue in one) but severely reduced protein levels (fibroblasts). A shorter protein product corresponding to the in-frame deletion variant was also detected.

The authors performed additional experiments to confirm small amounts of full-length protein produced by the start-lost variant. This was shown in SV40-transformed fibroblasts from the corresponding individual (treatment with a proteasome inhibitor resulted also in higher levels). Upon generation RPE1 cells using CRISPR for the start-lost variant, again, small amounts of full length protein were detected, which was not the case for complete knockout HAP1 cells. No shorter versions could be detected in the patient cells or RPE1 cells, arguing against utilization of an alternative start codon. (Use of non-AUG start codons discussed based on literature).

In line with small amounts of full-length protein the authors provided evidence for residual kinase activity for the start-loss variant (through proxy of phosphorylation of its substrate and use of a BUB1 kinase inhibitor). Cells from the individual with the frameshift variant and the splice variant had no residual kinase activity.

The authors provide evidence for mitotic defects in cells from both individuals with prolonged mitosis duration and chromosome segregation defects. Some patient-specific findings were thought to be related with BUB1 protein levels (affecting BUB1-mediated kinetochore recruitment of BUBR1, important for chromosome alignment) and others due to residual kinase activity [->phosphorylation of H2A at Threonine 120-> affecting centromeric recruitment of Aurora B, SGO1 (role in protection of centromeric cohesion), TOP2A (a protein preventing DNA breakage during sister chromatid separation), these correlated with high anaphase bridges (in P2), aneuploidy observed in lymphoblasts and primary fibroblasts from P2 but not P2's lymphocytes or lymphocytes from P1) and defective sister chromatid cohesion defects (in primary fibroblasts from P2, milder effect for P1).

Overall the authors provide evidence for overlapping clinical and cellular phenotype for this condition with primary microcephalies (MCPH - mutations in genes for mitotic regulators incl. kinetochore proteins or regulators of chromosome organization), mosaic variegated aneuploidy (biallelic variants in genes for kinetochore proteins, with random aneuploidies occurring in >5% cells of different tissues) and cohesinopathies (mostly Roberts or Warsaw breakage syndromes - characterized by cohesion loss and/or spontaneous railroad chromosomes).

Mouse model: Hmz disruption in mice is lethal shortly after E3.5 (cited PMID: 19772675), while a hypomorphic mutant mouse (lacking exons 2-3, expressing <5% of wt protein levels) is viable but exhibits increased tumorigenesis with aging and aneuploidy (cited PMID: 19117986). Mutant mice that lack kinase activity though with preserved Bub1 protein abundance, did not display increased susceptibility, despite substantial segregation errors and aneuploidies (cited PMID: 23209306).

The authors note that monoallelic germline BUB1 variants have been described in small number of individuals with CRC, exhibiting reduced expression levels and variegated aneuploidy in multiple tissues (cited PMID: 23747338) although the role of BUB1 is debated (cited PMIDs: 27713038, 29448935).

Based on the discussion, complete loss of BUB1 activity is presumed to be embryonically lethal based on the mouse study (PMID: 19772675) and reduced BUB1 expression associated with spontaneous miscarriages (cited PMID: 20643875, to my understanding in this study mRNA levels remained relatively constant despite reduced Bub1 protein levels, mRNA RT-PCR followed by sequencing revealed only 2 synonymous BUB1 variants).
Sources: Literature
Childhood solid tumours v2.33 TRIM28 Eleanor Williams Tag gene-checked tag was added to gene: TRIM28.
Hypertrophic cardiomyopathy v2.38 TRIM63 Eleanor Williams Tag gene-checked tag was added to gene: TRIM63.
Mitochondrial disorders v2.103 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35 617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873
Mitochondrial disorders v2.102 TRIT1 Eleanor Williams Tag gene-checked tag was added to gene: TRIT1.
Intellectual disability v3.1564 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from developmental delay to Combined oxidative phosphorylation deficiency 35, OMIM:617873
Intellectual disability v3.1563 TRIT1 Eleanor Williams Tag gene-checked tag was added to gene: TRIT1.
Possible mitochondrial disorder - nuclear genes v1.79 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, 617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873
Possible mitochondrial disorder - nuclear genes v1.78 TRIT1 Eleanor Williams Publications for gene: TRIT1 were set to
Possible mitochondrial disorder - nuclear genes v1.77 TRIT1 Eleanor Williams Tag gene-checked tag was added to gene: TRIT1.
Likely inborn error of metabolism v2.252 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM :617873
Likely inborn error of metabolism v2.251 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); No OMIM phenotype; Combined oxidative phosphorylation deficiency 35 617873 to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM:617873
Likely inborn error of metabolism v2.250 TRIT1 Eleanor Williams Tag gene-checked tag was added to gene: TRIT1.
Intellectual disability v3.1563 TRPM3 Eleanor Williams Tag gene-checked tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v2.519 TRPM3 Eleanor Williams Tag watchlist was removed from gene: TRPM3.
Tag gene-checked tag was added to gene: TRPM3.
Renal ciliopathies v1.64 TXNDC15 Eleanor Williams Tag gene-checked tag was added to gene: TXNDC15.
Neurological ciliopathies v1.31 TXNDC15 Eleanor Williams Tag gene-checked tag was added to gene: TXNDC15.
Rare multisystem ciliopathy disorders v1.160 TXNDC15 Eleanor Williams Tag gene-checked tag was added to gene: TXNDC15.
Fetal anomalies v1.860 TXNDC15 Eleanor Williams Tag gene-checked tag was added to gene: TXNDC15.
Unexplained young onset end-stage renal disease v1.36 TXNDC15 Eleanor Williams Tag gene-checked tag was added to gene: TXNDC15.
Limb disorders v2.78 TXNDC15 Eleanor Williams Tag gene-checked tag was added to gene: TXNDC15.
Mitochondrial disorders v2.102 NDUFAF8 Eleanor Williams Tag gene-checked tag was added to gene: NDUFAF8.
Possible mitochondrial disorder - nuclear genes v1.77 NDUFAF8 Eleanor Williams Tag gene-checked tag was added to gene: NDUFAF8.
Likely inborn error of metabolism v2.250 NDUFAF8 Eleanor Williams Tag gene-checked tag was added to gene: NDUFAF8.
Mitochondrial disorder with complex I deficiency v1.15 NDUFAF8 Eleanor Williams Tag gene-checked tag was added to gene: NDUFAF8.
Pulmonary fibrosis familial v0.9 NAF1 Eleanor Williams Tag gene-checked tag was added to gene: NAF1.
Haematological malignancies cancer susceptibility v2.30 NAF1 Eleanor Williams commented on gene: NAF1
Haematological malignancies cancer susceptibility v2.30 NAF1 Eleanor Williams Tag new-gene-name was removed from gene: NAF1.
Tag gene-checked tag was added to gene: NAF1.
Haematological malignancies cancer susceptibility v2.30 NAF1 Eleanor Williams Publications for gene: NAF1 were set to 28297620
Haematological malignancies for rare disease v1.12 NAF1 Eleanor Williams Publications for gene: NAF1 were set to 28297620
Haematological malignancies for rare disease v1.11 NAF1 Eleanor Williams Tag new-gene-name was removed from gene: NAF1.
Tag gene-checked tag was added to gene: NAF1.
Haematological malignancies for rare disease v1.11 NAF1 Eleanor Williams commented on gene: NAF1
Intellectual disability v3.1563 METTL5 Eleanor Williams Tag gene-checked tag was added to gene: METTL5.
Severe microcephaly v2.300 METTL5 Eleanor Williams Tag gene-checked tag was added to gene: METTL5.
DDG2P v2.72 LRRC56 Eleanor Williams Tag gene-checked tag was added to gene: LRRC56.
Fetal anomalies v1.860 LRRC56 Eleanor Williams Tag gene-checked tag was added to gene: LRRC56.
Respiratory ciliopathies including non-CF bronchiectasis v1.56 LRRC56 Eleanor Williams Tag gene-checked tag was added to gene: LRRC56.
Laterality disorders and isomerism v1.47 LRRC56 Eleanor Williams Tag gene-checked tag was added to gene: LRRC56.
Intellectual disability v3.1563 LMBRD2 Eleanor Williams Tag gene-checked tag was added to gene: LMBRD2.
Early onset or syndromic epilepsy v2.519 LMBRD2 Eleanor Williams Tag gene-checked tag was added to gene: LMBRD2.
Structural eye disease v1.122 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Intellectual disability v3.1563 WDR37 Eleanor Williams Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652
Intellectual disability v3.1562 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Early onset or syndromic epilepsy v2.519 WDR37 Eleanor Williams Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652
Early onset or syndromic epilepsy v2.518 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
DDG2P v2.72 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Severe microcephaly v2.300 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Intellectual disability v3.1562 ZNF526 Eleanor Williams Tag gene-checked tag was added to gene: ZNF526.
Severe microcephaly v2.300 ZNF526 Eleanor Williams Tag gene-checked tag was added to gene: ZNF526.
Bilateral congenital or childhood onset cataracts v2.108 ZNF526 Eleanor Williams Tag gene-checked tag was added to gene: ZNF526.
Adult onset dystonia, chorea or related movement disorder v1.170 KIAA1161 Eleanor Williams Tag gene-checked tag was added to gene: KIAA1161.
Adult onset neurodegenerative disorder v2.273 KIAA1161 Eleanor Williams Tag gene-checked tag was added to gene: KIAA1161.
Intracerebral calcification disorders v1.34 KIAA1161 Eleanor Williams Tag gene-checked tag was added to gene: KIAA1161.
Structural basal ganglia disorders v1.32 KIAA1161 Eleanor Williams Tag gene-checked tag was added to gene: KIAA1161.
White matter disorders and cerebral calcification - narrow panel v1.236 KIAA1161 Eleanor Williams Tag gene-checked tag was added to gene: KIAA1161.
Mitochondrial disorders v2.102 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Intellectual disability v3.1562 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Early onset or syndromic epilepsy v2.518 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Possible mitochondrial disorder - nuclear genes v1.77 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Childhood onset hereditary spastic paraplegia v2.137 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Severe microcephaly v2.300 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Paediatric disorders - additional genes v1.96 GREB1L Eleanor Williams Tag gene-checked tag was added to gene: GREB1L.
Monogenic hearing loss v2.242 GREB1L Eleanor Williams Tag gene-checked tag was added to gene: GREB1L.
Fetal anomalies v1.860 GREB1L Eleanor Williams Tag gene-checked tag was added to gene: GREB1L.
CAKUT v1.167 GREB1L Eleanor Williams Tag gene-checked tag was added to gene: GREB1L.
Intellectual disability v3.1562 FBRSL1 Eleanor Williams Tag gene-checked tag was added to gene: FBRSL1.
Severe microcephaly v2.300 FBRSL1 Eleanor Williams Tag gene-checked tag was added to gene: FBRSL1.
Intellectual disability v3.1562 CCDC47 Eleanor Williams Tag gene-checked tag was added to gene: CCDC47.
DDG2P v2.72 C11orf70 Eleanor Williams Tag gene-checked tag was added to gene: C11orf70.
Fetal anomalies v1.860 C11orf70 Eleanor Williams Tag gene-checked tag was added to gene: C11orf70.
Respiratory ciliopathies including non-CF bronchiectasis v1.56 C11orf70 Eleanor Williams Tag gene-checked tag was added to gene: C11orf70.
Laterality disorders and isomerism v1.47 C11orf70 Eleanor Williams Tag gene-checked tag was added to gene: C11orf70.
Arthrogryposis v3.159 ERGIC1 Eleanor Williams Tag gene-checked tag was added to gene: ERGIC1.
Fetal anomalies v1.860 EHBP1L1 Eleanor Williams Tag gene-checked tag was added to gene: EHBP1L1.
Likely inborn error of metabolism v2.250 EHBP1L1 Eleanor Williams Tag gene-checked tag was added to gene: EHBP1L1.
Fetal hydrops v1.55 EHBP1L1 Eleanor Williams Tag gene-checked tag was added to gene: EHBP1L1.
Intellectual disability v3.1562 CXorf56 Eleanor Williams Tag gene-checked tag was added to gene: CXorf56.
Intellectual disability v3.1562 CEP85L Eleanor Williams Tag gene-checked tag was added to gene: CEP85L.
Early onset or syndromic epilepsy v2.518 CEP85L Eleanor Williams Tag gene-checked tag was added to gene: CEP85L.
Malformations of cortical development v2.141 CEP85L Eleanor Williams Tag gene-checked tag was added to gene: CEP85L.
Pancreatitis v2.16 CELA3B Eleanor Williams Tag gene-checked tag was added to gene: CELA3B.
Hereditary neuropathy or pain disorder v1.101 C1orf194 Eleanor Williams Tag new-gene-name tag was added to gene: C1orf194.
Hereditary neuropathy or pain disorder v1.101 C1orf194 Eleanor Williams commented on gene: C1orf194
Hereditary neuropathy v1.453 C1orf194 Eleanor Williams commented on gene: C1orf194: Added new-gene-name tag, new approved HGNC gene symbol for C1orf194 is CFAP276.
Hereditary neuropathy v1.453 C1orf194 Eleanor Williams Tag new-gene-name tag was added to gene: C1orf194.
Hereditary neuropathy v1.453 C1orf194 Eleanor Williams commented on gene: C1orf194
Hereditary neuropathy v1.453 C1orf194 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: C1orf194.
Hereditary neuropathy v1.453 C1orf194 Eleanor Williams Tag gene-checked tag was added to gene: C1orf194.
Hereditary neuropathy or pain disorder v1.101 C1orf194 Eleanor Williams Tag gene-checked tag was added to gene: C1orf194.
Early onset or syndromic epilepsy v2.518 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Intellectual disability v3.1562 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis reviewed gene: CTR9: Rating: AMBER; 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: 35499524, 2815719, 25363760, 27479843, 25099282, 29292210; Phenotypes: Delayed speech and language development, Motor delay, Intellectual disability, Behavioral abnormality, Autistic behavior, Failure to thrive, Feeding difficulties, Abnormality of the cardiovascular system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis Deleted their review
Fetal anomalies v1.860 ARHGAP29 Catherine Snow Tag gene-checked tag was added to gene: ARHGAP29.
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis gene: CTR9 was added
gene: CTR9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTR9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210
Phenotypes for gene: CTR9 were set to Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Penetrance for gene: CTR9 were set to unknown
Mode of pathogenicity for gene: CTR9 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: CTR9 was set to AMBER
Added comment: Meuwissen, Verstraeten, Ranza et al (2022 - PMID: 35499524) describe the phenotype of 13 unrelated individuals harboring heterozygous - predominantly de novo - CTR9 missense variants.

Overlapping features included delayed speech and/or motor development (each in 9 cases) with the latter complicated by hypotonia or hyperlaxity in some cases. Balance or coordination problems were also reported in some. Variable degrees of ID ranging from mild to severe were observed in all individuals of relevant age except for 3 who however experienced impairment in other domains and/or learning difficulties (8/11 - 2 individuals were too young for evaluation). Few had evidence of regression. Other features included behavioral abnormalities (incl. ASD in 4), FTT/feeding problems (in 5), cardiovascular findings (in 4 - incl. infantile thoracic aortic aneurysm, VSD, pulm. valve stenosis, SVAS). The authors reported variable/nonspecific dysmorphic features.

WES revealed heterozygous CTR9 missense variants in all cases (NM_014633.5 as RefSeq). The variants occurred de novo in most (11/13) individuals with a one proband having inherited the variant from his affected parent. For one case, a single parental sample was available. Most SNVs were absent from gnomAD with the exception of c.1364A>G/p.Asn455Ser and c.2633G>A/p.Arg878Gln present once in the database (Z-score for CTR9: 4.3 / pLI : 1). The variants affected highly conserved residues with in silico predictions mostly in favor of a deleterious effect.

CTR9 encodes a subunit of the PAF1 complex (PAF1C) with the other subunits encoded by PAF1, LEO1, CDC73, RTF1 and WDR61/SKI8. The complex acts as a transcriptional regulator with CTR9 binding RNA polymerase II. The complex influences gene expression by promoting H2BK123 ubiquitylation, H3K4 and H3K36 methylation. In yeast, Paf1 and Ctr9 appear to mediate involvement of Paf1C in induction of mitophagy (several Refs provided).

In silico modeling: a group of N-terminal variants likely destabilize structure, another group possibly perturbs CTR9-PAF1 interactions and a 3rd class influences interactions with other subunits. p.Glu15Lys did not appear to influence protein stability.

Functional studies: H3K4/H3K36 methylation analysis, mitochondrial quality assessment and RNA-seq studies in fibroblasts did not provide conclusive evidence for downstream consequences of the variants (albeit a brain-specific effect - as demonstrated for other disorders – cannot be excluded).

Animal models: In zebrafish, the Paf1C complex has been shown to play a role in cardiac specification and heart morphogenesis with ctr9 mutants showing severe defects in morphogenesis of primitive heart tube (cited PMID: 21338598). This supports a role of the CTR9 variants in the cardiac abnormalities observed in 4 individuals. Although Paf1C zebrafish homologues are required for Notch-regulated transcription (cited PMID: 17721442), there was no supporting evidence from RNA-seq analyses performed by the authors. In Drosophila, Ctr9 has a key role at multiple stages of nervous system development in Drosophila (cited PMID: 27520958). In rat, Ctr9 is expressed in dopaminergic neurons, with its expression not restricted to the nucleus, regulating dopamine transporter activity (cited PMID: 26048990).

As commented, de novo CTR9 variants have been identified in indivdiduals with developmental disorders in larger cohorts, though without phenotypic details (DDD study - PMID:2815719, De Rubeis et al, 2014 - PMID: 25363760, Lelieveld et al PMID: 27479843) [ https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CTR9 ]

Two previous studies (Hanks et al, 2014 - PMID: 25099282, Martins et al 2018, PMID: 29292210) have identified individuals with pLoF variants [in almost all cases leading to skipping of ex9 e.g. NM_014633.4:c.958-9A>G or (RefSeq not provided) c.1194+2T>C, c.1194+3A>C, the single exception being c.106C>T/p.Q36*] in individuals and families with Wilms tumor after exclusion of other genetic causes. Analyses of tumor samples revealed in several of these cases either LOH (most commonly) or truncating variants as second hits. These individuals did not display neurodevelopmental phenotypes (despite detailed clinical information provided in the 2 studies). CTR9 is included in the gene panels for WT and Tumor predisposition - childhood onset with green rating. [In addition few individuals with hyperparathyroidism jaw tumor syndrome due to heterozygous variants in CDC73 - another subunit of the PAF1 complex - have been reported with WT].

Given these reports, commenting on the embryonic lethality of Ctr9 homozygous ko mice (MGI) and the observation of only missense variants in their cohort Meuwissen, Verstraeten, Ranza et al presume that a dominant-negative effect may apply for the variants they report.

Consider inclusion in the current panel with amber (variant effect/underlying mechanism unknown) or green rating (>3 individuals/families/variants, multiple reports, some supporting evidence from animal models).
Sources: Literature
Likely inborn error of metabolism v2.250 TRAP1 Catherine Snow Tag gene-checked tag was added to gene: TRAP1.
Likely inborn error of metabolism v2.250 MT-ND5 Catherine Snow Tag gene-checked tag was added to gene: MT-ND5.
Likely inborn error of metabolism v2.250 MT-ND4L Catherine Snow Tag gene-checked tag was added to gene: MT-ND4L.
Likely inborn error of metabolism v2.250 MT-ND4 Catherine Snow Tag gene-checked tag was added to gene: MT-ND4.
Likely inborn error of metabolism v2.250 MT-ND3 Catherine Snow Tag gene-checked tag was added to gene: MT-ND3.
Likely inborn error of metabolism v2.250 MT-ND2 Catherine Snow Tag gene-checked tag was added to gene: MT-ND2.
Likely inborn error of metabolism v2.250 MT-ND1 Catherine Snow Tag gene-checked tag was added to gene: MT-ND1.
Early onset or syndromic epilepsy v2.518 TUBGCP2 Catherine Snow Tag gene-checked tag was added to gene: TUBGCP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 ZNFX1 Catherine Snow Tag gene-checked tag was added to gene: ZNFX1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 TRIM22 Catherine Snow Tag gene-checked tag was added to gene: TRIM22.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 TNFRSF9 Catherine Snow Tag gene-checked tag was added to gene: TNFRSF9.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 C17orf62 Catherine Snow Tag gene-checked tag was added to gene: C17orf62.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 ALPI Catherine Snow Tag gene-checked tag was added to gene: ALPI.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 TLR7 Boaz Palterer changed review comment from: Missense variants of TLR7 that are gain-of-function were shown to cause SLE in two kindreds and a single patient.
Extensive functional data and mice model.; to: Missense variants of TLR7 that are gain-of-function (p.Y264H, p.F507L and p.R28G) were shown to cause SLE in two kindreds and a single patient.
Extensive functional data and mice model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 TLR7 Boaz Palterer reviewed gene: TLR7: 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: 35477763; Phenotypes: systemic lupus erythematosus, autoinflammatory, interferonopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.102 MT-TP Arina Puzriakova Tag gene-checked tag was added to gene: MT-TP.
DDG2P v2.72 MT-TP Arina Puzriakova Tag gene-checked tag was added to gene: MT-TP.
Likely inborn error of metabolism v2.250 MT-TP Arina Puzriakova Tag gene-checked tag was added to gene: MT-TP.
Undiagnosed metabolic disorders v1.532 MT-TP Arina Puzriakova Tag gene-checked tag was added to gene: MT-TP.
Mitochondrial disorders v2.102 MT-TN Arina Puzriakova Tag gene-checked tag was added to gene: MT-TN.
Likely inborn error of metabolism v2.250 MT-TN Arina Puzriakova Tag gene-checked tag was added to gene: MT-TN.
Undiagnosed metabolic disorders v1.532 MT-TN Arina Puzriakova Tag gene-checked tag was added to gene: MT-TN.
Mitochondrial disorders v2.102 MT-TM Arina Puzriakova Tag gene-checked tag was added to gene: MT-TM.
Likely inborn error of metabolism v2.250 MT-TM Arina Puzriakova Tag gene-checked tag was added to gene: MT-TM.
Undiagnosed metabolic disorders v1.532 MT-TM Arina Puzriakova Tag gene-checked tag was added to gene: MT-TM.
Mitochondrial disorders v2.102 MT-TL2 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL2.
Likely inborn error of metabolism v2.250 MT-TL2 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL2.
Undiagnosed metabolic disorders v1.532 MT-TL2 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL2.
Mitochondrial disorders v2.102 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Likely inborn error of metabolism v2.250 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Hereditary neuropathy v1.453 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Undiagnosed metabolic disorders v1.532 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Monogenic diabetes v2.47 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Familial diabetes v1.66 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.66 MT-TL1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-TL1.
Mitochondrial disorders v2.102 MT-TK Arina Puzriakova Tag gene-checked tag was added to gene: MT-TK.
Likely inborn error of metabolism v2.250 MT-TK Arina Puzriakova Tag gene-checked tag was added to gene: MT-TK.
Undiagnosed metabolic disorders v1.532 MT-TK Arina Puzriakova Tag gene-checked tag was added to gene: MT-TK.
Multiple lipomas v1.1 MT-TK Arina Puzriakova Tag gene-checked tag was added to gene: MT-TK.
Mitochondrial disorders v2.102 MT-TI Arina Puzriakova Tag gene-checked tag was added to gene: MT-TI.
Likely inborn error of metabolism v2.250 MT-TI Arina Puzriakova Tag gene-checked tag was added to gene: MT-TI.
Undiagnosed metabolic disorders v1.532 MT-TI Arina Puzriakova Tag gene-checked tag was added to gene: MT-TI.
Mitochondrial disorders v2.102 MT-TH Arina Puzriakova Tag gene-checked tag was added to gene: MT-TH.
Likely inborn error of metabolism v2.250 MT-TH Arina Puzriakova Tag gene-checked tag was added to gene: MT-TH.
Undiagnosed metabolic disorders v1.532 MT-TH Arina Puzriakova Tag gene-checked tag was added to gene: MT-TH.
Intellectual disability v3.1562 MPP5 Arina Puzriakova Tag gene-checked tag was added to gene: MPP5.
Intellectual disability v3.1562 LINGO4 Arina Puzriakova Tag gene-checked tag was added to gene: LINGO4.
Intellectual disability v3.1562 KLF7 Arina Puzriakova Tag gene-checked tag was added to gene: KLF7.
Intellectual disability v3.1562 KIF21B Arina Puzriakova Tag gene-checked tag was added to gene: KIF21B.
Intellectual disability v3.1562 KCND2 Arina Puzriakova Tag gene-checked tag was added to gene: KCND2.
Early onset or syndromic epilepsy v2.518 KCND2 Arina Puzriakova Tag gene-checked tag was added to gene: KCND2.
Intellectual disability v3.1562 JARID2 Arina Puzriakova Tag gene-checked tag was added to gene: JARID2.
COVID-19 research v1.126 INO80 Arina Puzriakova Tag gene-checked tag was added to gene: INO80.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 INO80 Arina Puzriakova Tag gene-checked tag was added to gene: INO80.
Intellectual disability v3.1562 AGO1 Eleanor Williams Tag gene-checked tag was added to gene: AGO1.
Paediatric disorders - additional genes v1.96 HYAL2 Arina Puzriakova Tag gene-checked tag was added to gene: HYAL2.
Clefting v2.67 HYAL2 Arina Puzriakova Tag gene-checked tag was added to gene: HYAL2.
Familial non syndromic congenital heart disease v1.75 HYAL2 Arina Puzriakova Tag gene-checked tag was added to gene: HYAL2.
Intellectual disability v3.1562 HNRNPH1 Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPH1.
Pituitary hormone deficiency v2.13 HID1 Arina Puzriakova Tag gene-checked tag was added to gene: HID1.
Early onset or syndromic epilepsy v2.518 HID1 Arina Puzriakova Tag gene-checked tag was added to gene: HID1.
Intellectual disability v3.1562 HID1 Arina Puzriakova Tag gene-checked tag was added to gene: HID1.
Childhood solid tumours cancer susceptibility v1.20 GPR161 Arina Puzriakova Tag gene-checked tag was added to gene: GPR161.
Childhood solid tumours v2.33 GPR161 Arina Puzriakova Tag gene-checked tag was added to gene: GPR161.
Structural eye disease v1.122 FZD5 Arina Puzriakova Tag gene-checked tag was added to gene: FZD5.
Ocular coloboma v1.46 FZD5 Arina Puzriakova Tag gene-checked tag was added to gene: FZD5.
Intellectual disability v3.1562 ZBTB7A Julia Baptista Deleted their review
Intellectual disability v3.1562 ZBTB7A Julia Baptista reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:34515416; Phenotypes: intellectual disability, macrocephaly, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Renal ciliopathies v1.64 DLG5 Sarah Leigh Tag gene-checked tag was added to gene: DLG5.
Renal ciliopathies v1.64 DLG5 Sarah Leigh Added comment: Comment on phenotypes: Phenotypes reported by Gen2Phen https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=DLG5
Renal ciliopathies v1.64 DLG5 Sarah Leigh Phenotypes for gene: DLG5 were changed from Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations to DLG5-associated developmental disorder (monoallelic); DLG5-associated developmental disorder (biallelic)
Cholestasis v1.107 CYP7A1 Sarah Leigh Tag gene-checked tag was added to gene: CYP7A1.
Cholestasis v1.107 CYP7A1 Sarah Leigh Publications for gene: CYP7A1 were set to 9802883
Mitochondrial disorders v2.102 MT-TG Arina Puzriakova Tag gene-checked tag was added to gene: MT-TG.
Likely inborn error of metabolism v2.250 MT-TG Arina Puzriakova Tag gene-checked tag was added to gene: MT-TG.
Undiagnosed metabolic disorders v1.532 MT-TG Arina Puzriakova Tag gene-checked tag was added to gene: MT-TG.
Mitochondrial disorders v2.102 MT-TF Arina Puzriakova Tag gene-checked tag was added to gene: MT-TF.
Likely inborn error of metabolism v2.250 MT-TF Arina Puzriakova Tag gene-checked tag was added to gene: MT-TF.
Undiagnosed metabolic disorders v1.532 MT-TF Arina Puzriakova Tag gene-checked tag was added to gene: MT-TF.
Unexplained young onset end-stage renal disease v1.36 MT-TF Arina Puzriakova Tag gene-checked tag was added to gene: MT-TF.
Tubulointerstitial kidney disease v1.20 MT-TF Arina Puzriakova Tag gene-checked tag was added to gene: MT-TF.
Mitochondrial disorders v2.102 MT-TE Arina Puzriakova Tag gene-checked tag was added to gene: MT-TE.
Likely inborn error of metabolism v2.250 MT-TE Arina Puzriakova Tag gene-checked tag was added to gene: MT-TE.
Undiagnosed metabolic disorders v1.532 MT-TE Arina Puzriakova Tag gene-checked tag was added to gene: MT-TE.
Mitochondrial disorders v2.102 MT-TD Arina Puzriakova Tag gene-checked tag was added to gene: MT-TD.
Likely inborn error of metabolism v2.250 MT-TD Arina Puzriakova Tag gene-checked tag was added to gene: MT-TD.
Undiagnosed metabolic disorders v1.532 MT-TD Arina Puzriakova Tag gene-checked tag was added to gene: MT-TD.
Mitochondrial disorders v2.102 MT-TC Arina Puzriakova Tag gene-checked tag was added to gene: MT-TC.
Likely inborn error of metabolism v2.250 MT-TC Arina Puzriakova Tag gene-checked tag was added to gene: MT-TC.
Undiagnosed metabolic disorders v1.532 MT-TC Arina Puzriakova Tag gene-checked tag was added to gene: MT-TC.
Mitochondrial disorders v2.102 MT-TA Arina Puzriakova Tag gene-checked tag was added to gene: MT-TA.
Likely inborn error of metabolism v2.250 MT-TA Arina Puzriakova Tag gene-checked tag was added to gene: MT-TA.
Undiagnosed metabolic disorders v1.532 MT-TA Arina Puzriakova Tag gene-checked tag was added to gene: MT-TA.
Bilateral congenital or childhood onset cataracts v2.108 CYP51A1 Sarah Leigh Publications for gene: CYP51A1 were set to 22935719; 25148791
Bilateral congenital or childhood onset cataracts v2.107 CYP51A1 Sarah Leigh Tag gene-checked tag was added to gene: CYP51A1.
Bilateral congenital or childhood onset cataracts v2.107 CYP51A1 Sarah Leigh Publications for gene: CYP51A1 were set to Aldahmesh (2012) Genet Med 14(12):955-962 - novel missense variant was reported to segregate with a cataract phenotype in a Saudi Arabian family. Gillespie et al (2014) Ophthlamol 121:2124-2137 (article not available for full text access).
Iron metabolism disorders - NOT common HFE mutations v1.33 CYBRD1 Sarah Leigh Tag gene-checked tag was added to gene: CYBRD1.
Mitochondrial disorders v2.102 MT-RNR1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-RNR1.
Monogenic hearing loss v2.242 MT-RNR1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-RNR1.
Hereditary neuropathy v1.453 MT-RNR1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-RNR1.
Likely inborn error of metabolism v2.250 MT-RNR1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-RNR1.
Undiagnosed metabolic disorders v1.532 MT-RNR1 Arina Puzriakova Tag gene-checked tag was added to gene: MT-RNR1.
Mitochondrial disorders v2.102 MT-ND6 Arina Puzriakova Tag gene-checked tag was added to gene: MT-ND6.
Likely inborn error of metabolism v2.250 MT-ND6 Arina Puzriakova Tag gene-checked tag was added to gene: MT-ND6.
Undiagnosed metabolic disorders v1.532 MT-ND6 Arina Puzriakova Tag gene-checked tag was added to gene: MT-ND6.
Optic neuropathy v2.68 MT-ND6 Arina Puzriakova Tag gene-checked tag was added to gene: MT-ND6.
Structural basal ganglia disorders v1.32 MT-ND6 Arina Puzriakova Tag gene-checked tag was added to gene: MT-ND6.
Mosaic skin disorders - deep sequencing v1.22 MAP3K3 Arina Puzriakova Tag gene-checked tag was added to gene: MAP3K3.
COVID-19 research v1.126 MAP3K14 Arina Puzriakova Tag gene-checked tag was added to gene: MAP3K14.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 MAP3K14 Arina Puzriakova Tag gene-checked tag was added to gene: MAP3K14.
Intellectual disability v3.1562 KCTD3 Arina Puzriakova Tag gene-checked tag was added to gene: KCTD3.
Early onset or syndromic epilepsy v2.518 KCTD3 Arina Puzriakova Tag gene-checked tag was added to gene: KCTD3.
Proteinuric renal disease v2.75 ITSN1 Arina Puzriakova Tag gene-checked tag was added to gene: ITSN1.
Unexplained young onset end-stage renal disease v1.36 ITSN1 Arina Puzriakova Tag gene-checked tag was added to gene: ITSN1.
Early onset or syndromic epilepsy v2.518 HNRNPR Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR.
DDG2P v2.72 HNRNPR Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR.
Intellectual disability v3.1562 HNRNPR Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR.
DDG2P v2.72 GNAI1 Arina Puzriakova Tag gene-checked tag was added to gene: GNAI1.
Intellectual disability v3.1562 GNAI1 Arina Puzriakova Tag gene-checked tag was added to gene: GNAI1.
Fetal anomalies v1.860 GNAI1 Arina Puzriakova Phenotypes for gene: GNAI1 were changed from GNAI1 syndrome to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, OMIM:619854
DDG2P v2.72 GNAI1 Arina Puzriakova Phenotypes for gene: GNAI1 were changed from GNAI1 syndrome to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, OMIM:619854
Intellectual disability v3.1562 GNAI1 Arina Puzriakova Phenotypes for gene: GNAI1 were changed from GNAI1 syndrome to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, OMIM:619854
Mosaic skin disorders - deep sequencing v1.22 GNA14 Arina Puzriakova Tag gene-checked tag was added to gene: GNA14.
Congenital hyperinsulinism v2.9 FOXA2 Arina Puzriakova Tag gene-checked tag was added to gene: FOXA2.
Pituitary hormone deficiency v2.13 FOXA2 Arina Puzriakova Tag gene-checked tag was added to gene: FOXA2.
Proteinuric renal disease v2.75 FAT1 Arina Puzriakova Tag gene-checked tag was added to gene: FAT1.
Structural eye disease v1.122 FAT1 Arina Puzriakova Tag gene-checked tag was added to gene: FAT1.
Anophthalmia or microphthalmia v1.45 FAT1 Arina Puzriakova Tag gene-checked tag was added to gene: FAT1.
Unexplained young onset end-stage renal disease v1.36 FAT1 Arina Puzriakova Tag gene-checked tag was added to gene: FAT1.
Childhood solid tumours v2.33 CTR9 Sarah Leigh Tag gene-checked tag was added to gene: CTR9.
Early onset or syndromic epilepsy v2.518 CSNK1G1 Sarah Leigh Tag gene-checked tag was added to gene: CSNK1G1.
Intellectual disability v3.1561 CSNK1G1 Sarah Leigh Tag gene-checked tag was added to gene: CSNK1G1.
Skeletal dysplasia v2.206 CSNK1G1 Sarah Leigh Tag gene-checked tag was added to gene: CSNK1G1.
Intellectual disability v3.1561 CSDE1 Sarah Leigh Tag gene-checked tag was added to gene: CSDE1.
Intellectual disability v3.1561 CHD5 Sarah Leigh Tag gene-checked tag was added to gene: CHD5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR2 Sarah Leigh Tag gene-checked tag was added to gene: CFHR2.
Paediatric disorders - additional genes v1.96 CDX1 Sarah Leigh Tag gene-checked tag was added to gene: CDX1.
Pain syndromes v1.12 SEPT9 Andrea Haworth commented on gene: SEPT9
Fetal anomalies v1.859 EXOC3L2 Arina Puzriakova Tag gene-checked tag was added to gene: EXOC3L2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 DNASE2 Arina Puzriakova Tag gene-checked tag was added to gene: DNASE2.
COVID-19 research v1.126 DNASE2 Arina Puzriakova Tag gene-checked tag was added to gene: DNASE2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.548 DNASE2 Arina Puzriakova Phenotypes for gene: DNASE2 were changed from Glomerulonephritis, arthropathy, vasculitis; Autoinflammatory Disorders; multisystem autoinflammatory syndrome; severe neonatal anemia; membranoproliferative glomerulonephritis; liver fibrosis; deforming arthropathy; SLE to Autoinflammatory-pancytopenia syndrome, OMIM:619858
COVID-19 research v1.126 DNASE2 Arina Puzriakova Phenotypes for gene: DNASE2 were changed from liver fibrosis; multisystem autoinflammatory syndrome; SLE; severe neonatal anemia; Autoinflammatory Disorders; deforming arthropathy; Glomerulonephritis, arthropathy, vasculitis; membranoproliferative glomerulonephritis to Autoinflammatory-pancytopenia syndrome, OMIM:619858
Primary immunodeficiency or monogenic inflammatory bowel disease v2.547 DNASE2 Arina Puzriakova Publications for gene: DNASE2 were set to 29259162
COVID-19 research v1.125 DNASE2 Arina Puzriakova Publications for gene: DNASE2 were set to 29259162
Fetal anomalies v1.859 DISP1 Arina Puzriakova commented on gene: DISP1: Added 'watchlist' tag as inclusion of this gene on the R85 Holoprosencephaly panel is currently under GMS review (TBC_NHSE) and the final decision should also be reflected on this panel once determined.
Fetal anomalies v1.859 DISP1 Arina Puzriakova Tag watchlist tag was added to gene: DISP1.
Fetal anomalies v1.859 DISP1 Arina Puzriakova Tag gene-checked tag was added to gene: DISP1.
Holoprosencephaly v2.27 DISP1 Arina Puzriakova Tag gene-checked tag was added to gene: DISP1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.546 DCLRE1B Arina Puzriakova Tag gene-checked tag was added to gene: DCLRE1B.
COVID-19 research v1.124 DCLRE1B Arina Puzriakova Tag gene-checked tag was added to gene: DCLRE1B.
Intellectual disability v3.1561 BRSK2 Sarah Leigh Tag gene-checked tag was added to gene: BRSK2.
Intellectual disability v3.1561 BRD4 Sarah Leigh Tag gene-checked tag was added to gene: BRD4.
Iron metabolism disorders - NOT common HFE mutations v1.33 BMP6 Sarah Leigh Tag gene-checked tag was added to gene: BMP6.
Pulmonary arterial hypertension v2.21 ATP13A3 Sarah Leigh Tag gene-checked tag was added to gene: ATP13A3.
Clefting v2.67 ARHGAP29 Sarah Leigh Tag gene-checked tag was added to gene: ARHGAP29.
Intellectual disability v3.1561 ACTL6A Sarah Leigh Tag gene-checked tag was added to gene: ACTL6A.
Paediatric or syndromic cardiomyopathy v1.70 MYH6 Sarah Leigh Publications for gene: MYH6 were set to
Paediatric or syndromic cardiomyopathy v1.69 MYH6 Sarah Leigh Phenotypes for gene: MYH6 were changed from Cardiomyopathy, dilated, 1EE; Cardiomyopathy, familial hypertrophic, 14 to Atrial septal defect 3, OMIM:614089; Cardiomyopathy, dilated, 1EE OMIM:613252; Cardiomyopathy, hypertrophic, 14, OMIM:613251; {Sick sinus syndrome 3}, OMIM:614090
Intellectual disability v3.1561 DNAH14 Konstantinos Varvagiannis gene: DNAH14 was added
gene: DNAH14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to 35438214
Penetrance for gene: DNAH14 were set to unknown
Review for gene: DNAH14 was set to RED
Added comment: Li et al (2022 - PMID: 35438214) describe 3 individuals harboring biallelic DNAH14 variants. In addition the authors perform a review of cases previously published in the literature.

The reported phenotype does not appear to be very consistent or specific (seizures with highly variable age of onset with or without DD / cognitive delay). Comparison with previously reported subjects (not further reviewed) - discussed in text and appearing mixed in table 1 - does not seem to support an overlapping phenotype.

The authors comment that DNAH14 encodes a heavy chain of axonemal dyneins. Little evidence is provided to support the role of the gene in the pathogenesis of the disorder and pathogenicity of the variants (ultra-rare and predicted in silico to be deleterious).
Sources: Literature
Intellectual disability v3.1561 DALRD3 Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Early onset or syndromic epilepsy v2.518 DALRD3 Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, it's product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. Specifically, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS3).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lylsates, with severe reduction (/loss) of m3C modification specific to the specific arginine tRNAs, which was not the case for others (eg. tRNA-Ser-UGA). These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (among others cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Early onset or syndromic epilepsy v2.518 DALRD3 Konstantinos Varvagiannis gene: DALRD3 was added
gene: DALRD3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910
Penetrance for gene: DALRD3 were set to Complete
Review for gene: DALRD3 was set to AMBER
Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, it's product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. Specifically, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS3).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lylsates, with severe reduction (/loss) of m3C modification specific to the specific arginine tRNAs, which was not the case for others (eg. tRNA-Ser-UGA). These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (among others cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature
Intellectual disability v3.1561 DALRD3 Konstantinos Varvagiannis gene: DALRD3 was added
gene: DALRD3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910
Penetrance for gene: DALRD3 were set to Complete
Review for gene: DALRD3 was set to AMBER
Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature
Early onset or syndromic epilepsy v2.518 DPH5 Konstantinos Varvagiannis gene: DPH5 was added
gene: DPH5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck
Penetrance for gene: DPH5 were set to unknown
Review for gene: DPH5 was set to AMBER
Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants.

As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date.

The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5).

WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser).

In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2.

In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression).

ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants.

Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice.

DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line.

The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653).

Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added).
Sources: Literature
Intellectual disability v3.1561 DPH5 Konstantinos Varvagiannis gene: DPH5 was added
gene: DPH5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck
Penetrance for gene: DPH5 were set to unknown
Review for gene: DPH5 was set to AMBER
Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants.

As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date.

The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5).

WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser).

In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2.

In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression).

ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants.

Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice.

DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line.

The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653).

Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added).
Sources: Literature
Intellectual disability v3.1561 CCDC82 Konstantinos Varvagiannis gene: CCDC82 was added
gene: CCDC82 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to 27457812; 28397838; 35118659; 35373332
Phenotypes for gene: CCDC82 were set to Global developmental delay; Intellectual disability; Spastic paraparesis
Penetrance for gene: CCDC82 were set to Complete
Review for gene: CCDC82 was set to AMBER
Added comment: The phenotype of individuals with biallelic CCDC82 variants has been reported - in most cases briefly - in the following reports (each summarizing the findings of previous ones):

Riazzudin et al (2017 - PMID: 27457812) in a large consanguineous pedigree from Pakistan (PKMR206) identified 4 individuals homozygous for a fs variant [NM_024725.3:c.373delG / p.(Asp125Ilefs*6)] (V3,V4,V5,V10). There was no other variant segregating with the phenotype of ID (Delayed CMS, moderate ID and speech delay probably common to all, V3,4,5 had also mild hypotonia and motor weakness). There was one unaffected sib tested (homozygous for ref. alelle). 2 further affected males (V1, V2) with similar phenotype were not tested.

Harripaul et al (2018 - PMID: 28397838) reported 2 sibs with nonsyndromic ID belonging to a consanguineous family (AS17) from the Middle-East. Both were homozygous for NM_024725.3:c.535C>T / p.Arg179*. The variant was confirmed with Sanger sequencing and parents were heterozygous carriers. Two additional affected sibs were probably not tested.

Yahia et al (2022 - PMID: 35118659) described 2 sibs belonging to a consanguineous family from Sudan. These presented global DD (last evaluation at 4y and 9m) and spasticity. There was a common history of infantile spasms with the elder developing GTC convulsions with spontaneous resolution. Additionaly, both presented microcephaly (<-2 and <-3SD). Exome sequencing revealed homozygosity for c.535C>T / p.Arg179* (previously reported by Harripaul et al). Sanger sequencing was used for confirmation and demonstration of carrier state of parents. Two similarly affected sibs were not available for testing.

Bauer et al (2022 - PMID: 35373332) reported a 21 y.o. male born to consanguineous parents from Pakistan. Features included short stature, ID, spastic paraparesis (at the age of 3y). Gelastic seizures were suspected but not confirmed (repeated normal EEGs). WES revealed homozygosity for a fs CCDC82 variant [NM_001318736.1:c.183del / p.(Phe61Leufs*27)] with Sanger confirmation in proband and heterozygous parents. There was another hmz variant, albeit classified as VUS and not thought to fit the clinical presentation.

As proposed by Bauer et al. overlapping features include spastic paraparesis, DD and dysmorphic features. As commented, CCDC82 encodes coiled-coil domain protein 82, a protein with unknown function.

Consider inclusion probably with amber rating (>3 individuals/families/variants, role of the gene not known, variant studies not performed to date, animal models not discussed).
Sources: Literature
Early onset or syndromic epilepsy v2.518 ENTPD1 Konstantinos Varvagiannis gene: ENTPD1 was added
gene: ENTPD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ENTPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENTPD1 were set to 35471564; 28742222
Phenotypes for gene: ENTPD1 were set to Spastic paraplegia 64, autosomal recessive, OMIM:615683
Penetrance for gene: ENTPD1 were set to Complete
Review for gene: ENTPD1 was set to AMBER
Added comment: Biallelic ENTPD1 pathogenic variants cause Spastic paraplegia 64, autosomal recessive (# 615683) with DD/ID being a universal feature as suggested by the study by Calame, Herman et al. Epilepsy was also reported in 7 unrelated individuals so far with supporting evidence also from mouse model.

Consider upgrade to green rating in the ID panel, inclusion in the epilepsy panel (amber/green). Also consider adding this gene in panels for white matter disorders (which does not appear to be the case so far).

-------

Calame, Herman et al (2022 - PMID:35471564) describe the phenotype of 27 individuals (from 17 unrelated families) with biallelic ENTPD1 pathogenic variants. The authors collected additional information from previously reported cases and summarize the core features of the disorder.

As they highlight, the disorder has a childhood onset, with DD/ID as a universal feature (27/27 or 36/36 considering cases from the literature), progressive spastic paraparesis (36/36) [On neurological examination, abnormal reflexes were common with hyperreflexia (8/36), hyporeflexia (5/36), areflexia (3/36) or both hyperreflexia and hypo/areflexia in 20, suggesting mixed upper and lower motor neuron dysfunction]. Other features included dysarthria (in 20/27 or 27/36 overall), white matter abnormalities on brain imaging (12/22 or 15/28, in 12-13 signal abnormalities in posterior limb of internal capsule), or dysmorphisms (13/27). Some individuals had evidence of neurocognitive regression (18/27 or 21/36). Epilepsy was reported in 7 unrelated individuals within the cohort (likely 7/25 as for 2 sibs from Fam11, this was NA). Previous studies had not reported this feature.

ENTPD1 encodes ectonucleoside triphosphate diphosphohydrolase 1, involved in hydrolysis of ATP to ADP (and ADP to AMP).

While previous studies identified 5 distinct variants (2 missense and 3 pLoF), the authors describe 12 novel variants 10 of which pLoF (stopgain, stoploss, splicing) and 2 missense (one SNV and one MNV).

In silico predictions were in favor of a deleterious effect. Almost all variants were ultrarare or absent from gnomAD, although 4 were recurrent ones [NM_001776.6]: c.1109T>A / p.(Leu370*) (possibly recurrent mutation found in 4 families from Persia/Poland), c.574-6_574-3del, c.770_771del / p.(Gly257Glufs*18) (possibly founder allele from the Iberian peninsula), c.1041del / p.(Ile348Phefs*19) (?founder allele in Persia).

Variant studies:
- c.574-6_574-3del : was shown to result to skipping (complete absence) of exon 6 (RNA extracted from a whole blood sample, followed by cDNA synthesis and Sanger seq using different primer sets).
- c.401T>G / p.Met134Arg : RT-qPCR of mRNA from patient lymphoblasts showed significantly reduced mRNA levels in individuals homozygous for this variant. Protein levels were also markedly decreased upon Western blot. ENTPD1 is essential for hydrolysis of ATP to ADP and ADP to AMP, with impairment of ATPase and ADPase activity (significantly decreased phosphate production) in patient lymphoblasts.
- c.185T>G / p.Leu62* : As ENTPD1 (also known as CD39) is highly expressed in lymphocytes and polymorphonuclear leukocytes, the authors used flow cytometry on whole blood from individuals hmz for this variant, carrier parents and controls, demonstrating complete absence of ENTPD1 positive cells in affected individuals. Immunohistochemistry for ENTPD1 using paraffin sections of sural nerve demonstrated complete absence of endo and epineural vascular staining (/lack of expression).

Untargeted metabolomic analyses were performed in plasma samples from 3 affected individuals. Consistent patterns of metabolic abnormalities with alterations in lipid, nucleotide and carbohydrate metabolism were observed. Some metabolite patterns or biomarkers were indicative of inflammatory state, liver disease, insulin resistance / metabolic syndrome.

The authors cite previous mouse models suggesting hepatocellular disfunction, impaired glucose homeostasis and intestinal inflammation in ectonucleotidase deficiency (probably not specific to Entpd1). Further, the authors cite a study by Lanser et al for Entpd1-/- mice exhibiting proepileptogenic activity (2017 - PMID: 28742222 / “Disruption of the ATP/adenosine balance in CD39(-/-) mice is associated with handling-induced seizures”).

In vitro studies using a cellular model of sympathetic neurons (nerve growth factor-differentiated PC12 cells) provided evidence that ENTPD1 expression levels modulate exocytic and ischemic neurotransmitter release (cited PMID: 21325440)

Overall, the authors propose accessible diagnostic biomarkers for the disorder (e.g. flow cytometry on periperal blood cells, immunochemistry of peripheral nerve biopsies, T2 hyperintense signal in posterior limb of internal capsule, diminished ATP/ADP breakdown in lymphoblast assays, alteration in metabolic pathways) and discuss potential future developments (ASOs for splicing variant, antagonism for purinergic receptor P2X7, etc).
Sources: Literature
Intellectual disability v3.1561 ENTPD1 Konstantinos Varvagiannis reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35471564; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 TFE3 Helen Lord reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v2.518 RNF13 Helen Lord changed review comment from: Agree there are 3 unrelated cases - so recladsify as green; to: Agree there are 3 unrelated cases - so reclassify as green
Early onset or syndromic epilepsy v2.518 RNF13 Helen Lord edited their review of gene: RNF13: Added comment: Agree there are 3 unrelated cases - so recladsify as green; Changed rating: GREEN
Early onset or syndromic epilepsy v2.518 PIGP Helen Lord edited their review of gene: PIGP: Added comment: Paper by Vetro et al 2020: 32042915 - Supports green rating; Changed rating: GREEN; Changed publications to: 28334793, 31139695, 32042915; Changed phenotypes to: developmental and epileptic encephalopathy 55
Early onset or syndromic epilepsy v2.518 KAT8 Helen Lord reviewed gene: KAT8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794431; Phenotypes: Li-Ghorgani-Weisz-Hubshman syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 KAT5 Helen Lord reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32822602; Phenotypes: Neurodevelopmental disorder with dysmorphic facies, sleep disturbance and brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 H3F3A Helen Lord reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Bryant-Li Bhoj neurodevelopmental syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 H3F3B Helen Lord reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Bryant-Li Bhoj neurodevelopmental syndrome 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 DMXL2 Helen Lord reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: developmental and epileptic encephalopathy 81; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 ASNS Helen Lord reviewed gene: ASNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24139043, 27469131, 29375865, 28776279, 29279279; Phenotypes: Asparagine Synthetase deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 ALKBH8 Helen Lord edited their review of gene: ALKBH8: Added comment: Saad et al, 2021: Third family of Egyptian descent harbouring a novel homozygous fs variant in the last exon of ALKBH8 - seen in two affected siblings, unaffected parents are het carriers. Parents are consanguineous. Variant likely to escape NMD.
Both proband and aff sister had global dev delay, autisitic features, - neither have epilepy or seizure-like episodes. Do have structural brain abnormalities including mild-mod cerebral volume loss, mild to mod cerebellar vermian hypoplasia, variable degrees of thinning of the corpus callosum and abnormal myelination for age on brain MRI.

Still would classify as amber...; Changed publications to: 33544954; Changed phenotypes to: Neurodevelopmental disorders
Early onset or syndromic epilepsy v2.518 CACNB4 Helen Lord edited their review of gene: CACNB4: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1561 PRODH Tracy Lester reviewed gene: PRODH: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disabilty; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1561 FBXO28 Konstantinos Varvagiannis gene: FBXO28 was added
gene: FBXO28 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXO28 were set to 30160831; 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy 100 (# 619777)
Penetrance for gene: FBXO28 were set to unknown
Review for gene: FBXO28 was set to GREEN
Added comment: Heterozygous pathogenic FBXO28 variants cause Developmental and epileptic encephalopathy 100 (# 619777).

At least 10 individuals with monoallelic missense / truncating FBXO28 variants have been reported. The subject with de novo frameshift variant initially reported by Balak et al (2018 - PMID:30160831) was included with additional clinical details in a recent report along with 9 further individuals (Schneider et al, 2021 - PMID: 33280099).

The phenotype corresponds to a developmental and epileptic encephalopathy with severe/profound ID. As discussed by Schneider et al, all individuals had DD prior to seizure onset which occurred at a median age of 22.5 months (range: 8m - 5y). The authors noted that missense variants may be associated with a milder phenotype (e.g. seizures occurred at the age of 4-5 years in 3 individuals).

Given these, FBXO28 appears to be relevant for inclusion in the current panel, with investigations prior to seizure onset.

As in the summary by Schneider et al, the gene encodes F-box only protein 28, a ubiquitin ligase promoting ubiquitination and degradation of phosphorylated proteins.

While FBXO28 has been suggested to have a critical role in 1q41q42 deletions (most spanning also WDR26) the authors note that a mechanism different than haploinsufficiency may underly FBXO28 encephalopathy.

Importantly, all 5 truncating variants reported (and 2/4 missense ones) occurred in the last exon, making these variants less susceptible to NMD. 2 other (of the 4) missense variants clustered in the F-box domain, which the authors hypothesize may correspond to a second pathogenic region.

7/9 variants arose de novo while 2 individuals had inherited a missense and a stopgain variant from mosaic unaffected parents (2.5% and 6%).

A comparison of the FBXO28-associated phenotype with the respective of 1q41q42 deletions and WDR26-related NDD is also made.

Consider inclusion in the ID panel with green (or amber) rating. Please consider inclusion in other possibly relevant panels (e.g. microcephaly (4/10), movement disorders, etc).
Sources: Literature
Intellectual disability v3.1561 GJB2 Dmitrijs Rots reviewed gene: GJB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1561 CCDC32 Konstantinos Varvagiannis reviewed gene: CCDC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 32307552, 35451546; Phenotypes: Cardiofacioneurodevelopmental syndrome (# 619123); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.302 FMR1 Dmitrijs Rots reviewed gene: FMR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.295 FMR1 Dmitrijs Rots reviewed gene: FMR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1561 CDK9 Konstantinos Varvagiannis changed review comment from: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature; to: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity.

Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824).
Sources: Literature
Intellectual disability v3.1561 CDK9 Konstantinos Varvagiannis gene: CDK9 was added
gene: CDK9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901
Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures
Penetrance for gene: CDK9 were set to Complete
Review for gene: CDK9 was set to GREEN
Added comment: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature
Intellectual disability v3.1561 TAB2 Andrea Haworth reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34741306; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.141 SOX11 Tracy Lester gene: SOX11 was added
gene: SOX11 was added to Malformations of cortical development. Sources: NHS GMS
Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX11 were set to 24886874; 26543203; 23556151
Phenotypes for gene: SOX11 were set to intellectual disability; facial dysmorphism; microcephaly; digit anomalies; central nervous system malformations
Penetrance for gene: SOX11 were set to unknown
Review for gene: SOX11 was set to GREEN
Added comment: Coffin-Siris syndrome is associated with brain malformations and variable ID. A pathogenic variant in this gene was identified in a case with brain malformations who had R87 panel applied but not R29 or R27. The gene is already green on these other panels.
Sources: NHS GMS
Haematological malignancies cancer susceptibility v2.29 UBA2 Sarah Leigh Phenotypes for gene: UBA2 were changed from lymphoblastic leukemia to acute lymphoblastic leukemia
Haematological malignancies cancer susceptibility v2.28 UBA2 Sarah Leigh gene: UBA2 was added
gene: UBA2 was added to Haematological malignancies cancer susceptibility. Sources: Literature
Mode of inheritance for gene: UBA2 was set to Other
Publications for gene: UBA2 were set to 34982829
Phenotypes for gene: UBA2 were set to lymphoblastic leukemia
Review for gene: UBA2 was set to RED
Added comment: PMID:34982829 reports: for the first time to our knowledge, provided evidence of a UBA2 variant (somatic frameshift deletion) preceding the well-established initiating event ETV6-RUNX1. Further, we suggest the UBA2 deletion exerted a leukemia predisposing effect and that its essential role in Small Ubiquitin-like Modifier (SUMO) attachment (SUMOylation), regulating nearly all physiological and pathological cellular processes such as DNA-repair by nonhomologous end joining, may hold a mechanistic explanation for the predisposition.
.
Sources: Literature
Inherited breast cancer and ovarian cancer v0.18 Eleanor Williams Panel status changed from internal to public
Pulmonary fibrosis familial v0.9 Eleanor Williams Panel status changed from internal to public
Malignant hyperthermia v0.5 Eleanor Williams Panel status changed from internal to public
Acute rhabdomyolysis v0.10 Eleanor Williams Panel status changed from internal to public
Autoinflammatory disorders v0.37 Eleanor Williams Panel status changed from internal to public
Multi locus imprinting disorders v0.14 Eleanor Williams Panel status changed from internal to public
Early onset or syndromic epilepsy v2.518 GLRA2 Konstantinos Varvagiannis gene: GLRA2 was added
gene: GLRA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GLRA2 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: GLRA2 were set to 20531469; 20479760; 26370147; 28588452; 35294868
Phenotypes for gene: GLRA2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Microcephaly; Abnormality of eye movement
Penetrance for gene: GLRA2 were set to unknown
Mode of pathogenicity for gene: GLRA2 was set to Other
Review for gene: GLRA2 was set to AMBER
Added comment: Heterozygous or hemizygous pathogenic GLRA2 variants cause Intellectual developmental disorder, X-linked, syndromic, Pilorge type (# 301076) as summarized in a recent OMIM entry.

The phenotype is characterized by DD with variably impaired intellectual development, behavioral abnormalities (autistic features in some), variable ocular findings (nystagmus, strabismus, oculomotor apraxia) and seizures in some [ 6/13 in Ref4 ].

GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth.

Animal models support the role of the gene in CNS.

Studies have been performed for several of the variants reported to date (in all cases missense and a htz deletion of the last 2 exons).

As summarized by OMIM, most affected females carry de novo htz missense GoF variants, and most affected males inherited hemizygous LoF ones.

XCI has not been studied in most htz (affected/unaffected) females (with the exception of the del in Ref2, see also Ref3).

Details provided below.

(Note: Most articles refer to variants using HGVS nomenclature while few without incl. the signal peptide eg. p.Arg350Leu corresponding to Arg323Leu).

Consider inclusion in the current panel with amber/green rating.


[1]----
Piton et al (2011 - PMID: 20479760) sequenced 111 X-linked synaptic genes in a cohort of 142 individuals with ASD and identified a female (S00125) harboring Arg350Leu (NM_002063 chrX:14618871 G/T), inherited from her mother (no clinical information provided). Functional evaluation of the variant was performed in a later publication (Ref3), providing additional clinical details on the proband.

[2]----
Pilorge et al (2016 - PMID: 26370147) review the role of glycine receptors (GlyRs). These typically consist of pentameric combinations of alpha (α1-α4) and beta (β) subunits and form a pore that controls transmembrane flux of chloride. GlyRs can be formed either as homomers comprising five α subunits or as heteromers of α and β subunits (in 2:3 or 3:2 stoichiometry). Each subunit has an N-terminal extracellular domain with the ligand-binding site and 4 transmembrane domains. GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth. The authors discuss the role of glycine as inhibitory neurotransmitter in adult CNS and depolarizing/excitatory action in immature neurons, as well as the role of GlyR α2 in proliferation and neuronal migration during cortical development.

The authors previously (2010 - PMID: 20531469) identified a boy with ASD, language delay and low average IQ (verbal 93, performance 75, full-scale IQ 82) harboring a 142 kb microdeletion spanning the last 2 exons of GRLA2 (hg19 - chrX:14693216-14836199). This CNV was confirmed with qPCR and the breakpoints localized to intron 7 after sequencing. Reverse transcription of mRNA from blood revealed presence of a truncated transcript in the child suggestive of little or no NMD. In the mother, the non-truncated transcript was amplified. Further it was shown that the product leaded to incorporation of intron 7, with inclusion of 5 residues followed by a stop codon. The mother had a normal, non-skewed XCI. Previous testing had excluded an FMR1 expansion.

Screening of 400 males with ASD identified a further male with de novo missense SNV (NM_002063.3:c.458G>A / p.Arg153Gln). This child had non-syndromic autism, severe language delay, mild ID (fs IQ 63) and GTC seizures with onset at 18y. Previous testing incl. a normal karyotype, FMR1 analysis, and CMA. The boy had an older sister with ASD, not harboring the same GLRA2 variant (interpreted in the context of intrafamilial genetic heterogeneity for ASD).

The authors also studied a dn missense variant (NM_001118886.1:c.407A>G / p.Asn136Ser) previously reported in a proband with autism (11842.p2 - Iossifov et al, 2014 - PMID: 25363768).

In vitro studies demonstrated that the 3 aforementioned variants impaired GlyR2 α2 function:
- The authors generated constructs for wt, the deletion (of last 2 exons) and Arg153Gln and performed co-transfection with EGFP cDNA in Chinese hamster ovary (CHO) cells. While wt and Arg153Gln were observed at the plasma membrane of transfected cells, the del was undetectable at the cell surface and was mislocalized in the cytoplasm (as also expected by loss of the transmembrane domains).
- Upon isolation of biotinylated surface receptors and western blot, Arg153Gln was shown to result to 56% decreased surface expression compared to wt, while the intracellular fragment was also reduced by 32% suggesting impaired synthesis or degradation. Asn136Ser had 67% lower surface (and 15% lower intracellular) expression.
- Whole-cell patch clamp recordings of transfected CHO cells suggested that the minimum concentration of glycine to evoke whole-cell current was ~100 higher for Arg153Gln compared to wt. High concentrations of glycine were unable to evoke any current in the case of the deletion (due to loss of surface expression). Asn136Ser also reduced glycine sensitivity (14x increase in EC50).

Zebrafish studies for glra2 and the del or Arg153Gln variants:
Morpholino mediated knockdown of glra2 led to hyperbranching of spinal motor axons compared to ctrls. Co-injection of human wt mRNA with glra2 morpholino, rescued the aberrant branching phenotype which was not the case for the 2 variants.

Glra2 ko mouse model (also on chrX):
- Mutant mice (Glra2-/Y) had normal adult body, brain weight, were fertile and had a normal lifespan. They displayed no differences in locomotor activity, or social behavior compared to wt. They however exhibited impaired learning and memory in the novel object recognition task (spatial learning and memory in the novel location recognition task and Morris water maze were N).
- Long-term potentiation in prefrontal cortex after high frequency stimulation was significantly impaired in mutant mice compared to wt, overall supporting that impaired glycinergic signaling results in abnormal synaptic plasticity in this relevant for ASD region.

[3]----
Zhang et al (2017 - PMID: 28588452) determined the functional effects of Arg350Leu which was reported by Piton et al (Arg323Leu without the signal peptide).

The authors provide further clinical details on this female with autism, macrocephaly, loss of acquired words, seizures, mild motor delay and hypothyroidism. The mother of the, also carrier of the SNV, was reportedly unaffected.

The potency of glycine in activating recombinant homomeric α2 and heteromeric α2β receptors was examined by whole-cell patch-clamp recording (HEK293 cells).

In homo-/ and heteromeric receptors this variant resulted in small decrease in glycine sensitivity with peak currents not significantly different compared to wt (the latter suggestive of normal surface expression).

This variant resulted in prolonged inhibitory postsynaptic currents (IPSCs) with ~2-fold slower rise and decay times, while IPSC amplitude did not differ significantly. Overall, the slowed decay times, prolongation of active periods and small but significantly increased conductance of mutant channels suggested that this variant exerts a gain-of-function effect.

The authors briefly cite a study by Cotton et al (2015, PMID: 25381334) providing evidence that GLRA2 escapes XCI in the vast majority of tissues and brain.

[4]----
Marcogliese et al (2022 - PMID: 35294868) functionally tested the effects of missense DNM observed in individuals with ASD diagnosis in Drosophila. The authors generated TG4 (MiMIC cassette) fly mutants for candidate ASD genes (creating LoF alleles for the respective genes). Using a GAL4/UAS system with human cDNA constructs for reference/variants they performed the rescue/overexpression assays to study the functional consequences.

Flies expressing human ref GLRA2 cDNA failed to copulate but exhibited normal movement. Flies for Asn136Ser (a variant reported by Iossifov et al, 2014 - PMID: 25363768) copulated similar to the TG4 mutant providing evidence for a LoF effect of this variant.

Upon GAL4/UAS expression and co-staining with neuronal (Elav) and glial (Repo) nuclear markers, GLRA2 was shown to be expressed in CNS with expression in a subset of neurons and in some glia.

Upon ubiquitous overexpression of human reference or variant cDNA, Asn136Ser also behaved as a LoF allele.

Based on the evidence on this gene, and following re-analyses of exome data, GeneMatcher collaborations etc, the authors identified 13 additional unrelated subjects harboring GLRA2 variants (8 females/5 males). These had DD/ID of variable severity (13/13) w/wo autistic features (in 4 or 5), microcephaly (4-5/13 all females), epilepsy (6/13 - both sexes) and ocular manifestations (10/13 - incl. nystagmus, strabismus, etc). Hypotonia/incoordination was observed in 7/13.

All females had dn missense variants (8/8, NM_001118886.1:c.887C>T/p.Thr296Met in 6/8, others: c.140T>C/p.Phe47Ser, c.777C>G/p.Ile259Met), while all males had inherited missense SNVs from their unaffected mothers (p.Arg252Cys, p.Ala288Thr, p.Pro396Thr, p.Pro400Leu, p.Arg445Gln).

The authors studied an variant which was recurrent in females (Thr296Met) and another found in a male (Arg252Cys). Upon overexpression, the latter behaved - similarly to Asn136Ser - as LoF allele, while Thr296Met did not differ significantly from reference.

Structural modeling suggested that Thr296 is adjacent to a residue important for keeping the ion pore in closed conformation.

Upon pnr-GAL4 (over)expression in the dorsolateral stripe in the notum, Thr296Met caused lethality, which was not the case for the reference. When expressed at lower levels, Thr296Met formation of melanized nodules in thorax, a phenotype not previously observed upon overexpression of ref/other variants.

The authors performed ERGs in fly eyes. They first used a pan-neuronal driver (nSyb-GAL) leading to GLRA2 ref / variant expression in pre-synaptic photoreceptors and post-synaptic neurons. A significant increase of "OFF" transients was observed for Thr296Met, suggesting increase in synaptic transmission and a GoF effect. Expression limited to pre-synaptic photoreceptors (Rh1-GAL4 driver) did not lead to significant differences compared to ref allele, while Arg252Cys was associated with decreased amplitudes of "OFF" transients, suggestive of decreased synaptic transmission and confirming a LoF effect.

Marcogliese et al conclude that reduced GLRA2 activity can lead to disease in males but can be tolerated in htz females (as was the case for asymptomatic mothers), while GoF variants leading to overactivation of the channel could be overrepresented in affected females.
Sources: Literature
Intellectual disability v3.1561 GLRA2 Konstantinos Varvagiannis reviewed gene: GLRA2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20531469, 20479760, 26370147, 28588452, 35294868; Phenotypes: Global developmental delay, Intellectual disability, Autism, Behavioral abnormality, Seizures, Microcephaly, Abnormality of eye movement; 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 v3.1561 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Septooptic dysplasia, 182230Pituitary hormone deficiency, combined, 5, 182230Growth hormone deficiency with pituitary anomalies, 182230; HESX1-RELATED COMBINED PITUITARY HORMONE DEFICIENCY to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
Hypogonadotropic hypogonadism v1.35 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Pituitary hormone deficiency, combined, 5, Growth hormone deficiency with pituitary anomalies, Septooptic dysplasia, 182230 to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
Pituitary hormone deficiency v2.13 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Growth hormone deficiency with pituitary anomalies (182230); Pituitary hormone deficiency, combined, 5 (182230) to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
IUGR and IGF abnormalities v1.53 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Septo-optic dysplasia; variable involvement of pituitary hormones to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
Congenital hypothyroidism v2.11 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Panhypopiuitarism; GH and evolving TSH, ACTH, LH/FSH deficiency; septo-optic dysplasia; anterior pituitary, ectopic posterior pituitary; agenesis of corpus callous; optic nerve hypoplasia; Pituitary hormone deficiency, combined, 5, 182230 to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
Inherited bleeding disorders v1.169 GP1BB Arina Puzriakova Publications for gene: GP1BB were set to 9116284; 10887115; 8703016; 28064200
Bleeding and platelet disorders v1.40 GP1BB Arina Puzriakova Publications for gene: GP1BB were set to 24934643; 9616133; 21357716
Cytopenia - NOT Fanconi anaemia v1.69 GP1BB Arina Puzriakova Publications for gene: GP1BB were set to
Cytopenia - NOT Fanconi anaemia v1.68 GP1BB Arina Puzriakova Classified gene: GP1BB as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.68 GP1BB Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS review. Variants are associated with Bernard-Soulier syndrome characterised by thrombocytopenia (within the scope of this panel), giant platelets and bleeding tendency. Sufficient cases for both inheritance patterns to rate as green with an AD/AR mode of inheritance.
Cytopenia - NOT Fanconi anaemia v1.68 GP1BB Arina Puzriakova Gene: gp1bb has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.67 GP1BB Arina Puzriakova Tag Q2_22_rating tag was added to gene: GP1BB.
Cytopenia - NOT Fanconi anaemia v1.67 GP1BB Arina Puzriakova Mode of inheritance for gene: GP1BB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.66 GP1BB Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic' to align with the MOI set on other panels (Inherited bleeding disorders, Bleeding and platelet disorders). PMID:28064200 provides evidence for AD inheritance of macrothrombocytopenia.
Cytopenia - NOT Fanconi anaemia v1.66 GP1BB Arina Puzriakova Mode of inheritance for gene: GP1BB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.65 GP1BB Arina Puzriakova Phenotypes for gene: GP1BB were changed from Bernard-Soulier syndrome, type B, 231200; Mild macrothrombocytopenia to Bernard-Soulier syndrome, type B, OMIM:231200; Giant platelet disorder, isolated, OMIM:231200; Macrothrombocytopenia
Bleeding and platelet disorders v1.39 GP1BB Arina Puzriakova Phenotypes for gene: GP1BB were changed from BSS; 231200 BERNARD-SOULIER SYNDROME; 231200BERNARD-SOULIER SYNDROME to Bernard-Soulier syndrome, type B, OMIM:231200; Giant platelet disorder, isolated, OMIM:231200; Macrothrombocytopenia
Inherited bleeding disorders v1.168 GP1BB Arina Puzriakova Phenotypes for gene: GP1BB were changed from Bernard-Soulier syndrome, type B (BIALLELIC, autosomal or pseudoautosomal); Giant platelet disorder, isolated (AR); 231200; Bernard-Soulier syndrome; Macrothrombocytopenia (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown) to Bernard-Soulier syndrome, type B, OMIM:231200; Giant platelet disorder, isolated, OMIM:231200; Macrothrombocytopenia
Mitochondrial disorders v2.102 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812 to Fumarase deficiency, OMIM:606812
Intellectual disability v3.1560 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812Leiomyomatosis and renal cell cancer, 150800; FUMARASE DEFICIENCY to Fumarase deficiency, OMIM:606812
Early onset or syndromic epilepsy v2.518 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812; Seizures to Fumarase deficiency, OMIM:606812
Fetal anomalies v1.859 FH Arina Puzriakova Phenotypes for gene: FH were changed from FUMARASE DEFICIENCY to Fumarase deficiency, OMIM:606812
Possible mitochondrial disorder - nuclear genes v1.77 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency 606812 to Fumarase deficiency, OMIM:606812
Likely inborn error of metabolism v2.250 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812; Fumarase deficiency (Disorders of the citric acid cycle) to Fumarase deficiency, OMIM:606812; Disorders of the citric acid cycle
Undiagnosed metabolic disorders v1.532 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency (Disorders of the citric acid cycle); Fumarase deficiency, 606812 to Fumarase deficiency, OMIM:606812; Disorders of the citric acid cycle
Adult solid tumours cancer susceptibility v2.21 FH Arina Puzriakova Phenotypes for gene: FH were changed from Hereditary Leiomyomatosis and Renal Cell Cancer to Leiomyomatosis and renal cell cancer, OMIM:150800
Adult solid tumours for rare disease v1.33 FH Arina Puzriakova Phenotypes for gene: FH were changed from Hereditary Leiomyomatosis and Renal Cell Cancer to Leiomyomatosis and renal cell cancer, OMIM:150800
Skeletal dysplasia v2.206 KDELR2 Arina Puzriakova Phenotypes for gene: KDELR2 were changed from Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms; Osteogenesis imperfecta to Osteogenesis imperfecta, type XXI, OMIM:619131; Increased susceptibility to fractures; Joint hypermobility; Scoliosis; Bowing of the legs and arms
Osteogenesis imperfecta v2.48 KDELR2 Arina Puzriakova Phenotypes for gene: KDELR2 were changed from Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms; Osteogenesis imperfecta to Osteogenesis imperfecta, type XXI, OMIM:619131; Increased susceptibility to fractures; Joint hypermobility; Scoliosis; Bowing of the legs and arms
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh changed review comment from: Comment on phenotypes: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7; to: Comment on phenotypes: Previous phenotype entry: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh edited their review of gene: SLC16A1: Changed phenotypes to: Erythrocyte lactate transporter defect, OMIM:245340, Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021, Monocarboxylate transporter 1 deficiency, OMIM:616095; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.249 SLC16A1 Sarah Leigh changed review comment from: Comment on phenotypes: Hyperinsulinemic hypoglycemia, familial, 7;mainly ketosis with borderline reduction in glucose; to: Comment on phenotypes: Previous phenotype entry: Hyperinsulinemic hypoglycemia, familial, 7;mainly ketosis with borderline reduction in glucose
Likely inborn error of metabolism v2.249 SLC16A1 Sarah Leigh edited their review of gene: SLC16A1: Changed phenotypes to: Erythrocyte lactate transporter defect, OMIM:245340, Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021, Monocarboxylate transporter 1 deficiency, OMIM:616095; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ketotic hypoglycaemia v1.6 SLC16A1 Sarah Leigh changed review comment from: Comment on phenotypes: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7; to: Comment on phenotypes: Previous phenotype entry: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7
Ketotic hypoglycaemia v1.6 SLC16A1 Sarah Leigh edited their review of gene: SLC16A1: Changed phenotypes to: Erythrocyte lactate transporter defect, OMIM:245340, Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021, Monocarboxylate transporter 1 deficiency, OMIM:616095; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v1.124 FASLG Eleanor Williams Added comment: Comment on mode of inheritance: Changing the MOI to Both mono and biallelic as there are cases reported with both modes of inheritance, although a stronger phenotype in the case of homozygous variants. See the review on https://panelapp.genomicsengland.co.uk/panels/398/gene/FASLG/ for more detail.
COVID-19 research v1.124 FASLG Eleanor Williams Mode of inheritance for gene: FASLG was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.546 FASLG Eleanor Williams Added comment: Comment on mode of inheritance: There are 3 cases with Autoimmune lymphoproliferative syndrome reported with homozygous variants in FASLG but also 2 reports of milder cases with heterozygous variants (not fully penetrant) so a change of mode of inheritance to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" should be considered following GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.546 FASLG Eleanor Williams Mode of inheritance for gene: FASLG was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.545 FASLG Eleanor Williams Tag Q2_22_MOI tag was added to gene: FASLG.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.545 FASLG Eleanor Williams Added comment: Comment on publications: Removed publications with the following PMIDS as not specifically about patients with variants in FASLG: 26907631;16537120;8806292;22983577;16394653
Primary immunodeficiency or monogenic inflammatory bowel disease v2.545 FASLG Eleanor Williams Publications for gene: FASLG were set to 8806292; 16537120; 16394653; 8787672; 20301287; 17605793; 26907631; 27848183; 25451160; 22857792; 7511063; 22983577
Ketotic hypoglycaemia v1.6 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7
Ketotic hypoglycaemia v1.6 SLC16A1 Sarah Leigh Phenotypes for gene: SLC16A1 were changed from mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7 to Erythrocyte lactate transporter defect, OMIM:245340; Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Monocarboxylate transporter 1 deficiency, OMIM:616095
Likely inborn error of metabolism v2.249 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: Hyperinsulinemic hypoglycemia, familial, 7;mainly ketosis with borderline reduction in glucose
Likely inborn error of metabolism v2.249 SLC16A1 Sarah Leigh Phenotypes for gene: SLC16A1 were changed from Hyperinsulinemic hypoglycemia, familial, 7; mainly ketosis with borderline reduction in glucose to Erythrocyte lactate transporter defect, OMIM:245340; Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Monocarboxylate transporter 1 deficiency, OMIM:616095
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh Phenotypes for gene: SLC16A1 were changed from mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7 to Erythrocyte lactate transporter defect, OMIM:245340; Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Monocarboxylate transporter 1 deficiency, OMIM:616095
Congenital hyperinsulinism v2.9 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: Hyperinsulinism, Dominant;Erythrocyte lactate transporter defect, 245340;Autosomal dominant exercise-induced hyperinsulinism
Congenital hyperinsulinism v2.9 SLC16A1 Sarah Leigh Phenotypes for gene: SLC16A1 were changed from Hyperinsulinism, Dominant; Erythrocyte lactate transporter defect, 245340; Autosomal dominant exercise-induced hyperinsulinism to Erythrocyte lactate transporter defect, OMIM:245340; Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Monocarboxylate transporter 1 deficiency, OMIM:616095
Congenital hyperinsulinism v2.8 SLC16A1 Sarah Leigh reviewed gene: SLC16A1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Erythrocyte lactate transporter defect, OMIM:245340, Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021, Monocarboxylate transporter 1 deficiency, OMIM:616095; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.101 SH3TC2 Sarah Leigh Phenotypes for gene: SH3TC2 were changed from Charcot Marie Tooth disease, type 4C, 601596; Mononeuropathy of the median nerve, mild, 613353 to Charcot-Marie-Tooth disease, type 4C, OMIM:601596; Mononeuropathy of the median nerve, mild, OMIM:613353
Hereditary neuropathy v1.453 SH3TC2 Sarah Leigh Phenotypes for gene: SH3TC2 were changed from Mononeuropathy of the median nerve, mild, 613353; Charcot Marie Tooth disease, type 4C, 601596 to Charcot-Marie-Tooth disease, type 4C, OMIM:601596; Mononeuropathy of the median nerve, mild, OMIM:613353
Hereditary neuropathy or pain disorder v1.100 SH3TC2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: SH3TC2.
Hereditary neuropathy v1.452 SH3TC2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: SH3TC2.
Hereditary neuropathy v1.452 SH3TC2 Sarah Leigh reviewed gene: SH3TC2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 4C, OMIM:601596, Mononeuropathy of the median nerve, mild, OMIM:613353; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.100 SH3TC2 Sarah Leigh reviewed gene: SH3TC2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 4C, OMIM:601596, Mononeuropathy of the median nerve, mild, OMIM:613353; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.530 SETX Sarah Leigh Phenotypes for gene: SETX were changed from Secondary CoQ10 deficiency (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Amyotrophic lateral sclerosis/motor neuron disease; Charcot-Marie-Tooth disease; Hereditary ataxia to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002; Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Undiagnosed metabolic disorders v1.529 SETX Sarah Leigh edited their review of gene: SETX: Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002, Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Likely inborn error of metabolism v2.248 SETX Sarah Leigh Phenotypes for gene: SETX were changed from Secondary CoQ10 deficiency (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Charcot-Marie-Tooth disease; Hereditary ataxia; Amyotrophic lateral sclerosis/motor neuron disease to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002; Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Likely inborn error of metabolism v2.247 SETX Sarah Leigh edited their review of gene: SETX: Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002, Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Hereditary neuropathy v1.452 SETX Sarah Leigh Tag Q2_22_MOI tag was added to gene: SETX.
Hereditary neuropathy v1.452 SETX Sarah Leigh edited their review of gene: SETX: Added comment: The Q2_22_MOI tag has been added to this gene as the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as both Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002;Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433 are relevant to this panel.; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002, Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.452 SETX Sarah Leigh Phenotypes for gene: SETX were changed from to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002; Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Hereditary neuropathy v1.451 SETX Sarah Leigh Added comment: Comment on publications: PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant;PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.
Hereditary neuropathy v1.451 SETX Sarah Leigh Publications for gene: SETX were set to PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant; PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.
Hereditary neuropathy or pain disorder v1.100 SETX Sarah Leigh edited their review of gene: SETX: Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.544 FASLG Eleanor Williams Phenotypes for gene: FASLG were changed from Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; SLE to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; systemic lupus erythematosus (SLE)
Hereditary neuropathy or pain disorder v1.100 SETX Sarah Leigh Added comment: Comment on phenotypes: SETX variants are also associated with Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433, but this condition is not relevant to this narrow panel.
Hereditary neuropathy or pain disorder v1.100 SETX Sarah Leigh Phenotypes for gene: SETX were changed from to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002
Primary immunodeficiency or monogenic inflammatory bowel disease v2.543 FASLG Eleanor Williams Phenotypes for gene: FASLG were changed from Autoimmune lymphoproliferative syndrome, type IB, 601859; Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG); Autoimmune lymphoproliferative syndrome (ALPS); Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated; Diseases of Immune Dysregulation to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; SLE
Corneal dystrophy v1.13 COL17A1 Arina Puzriakova Phenotypes for gene: COL17A1 were changed from Epithelial recurrent erosion dystrophy 122400 to Epithelial recurrent erosion dystrophy, OMIM:122400
Hereditary neuropathy or pain disorder v1.99 SETX Sarah Leigh Added comment: Comment on publications: PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.;PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant
Hereditary neuropathy or pain disorder v1.99 SETX Sarah Leigh Publications for gene: SETX were set to PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.; PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant
Amelogenesis imperfecta v2.20 COL17A1 Arina Puzriakova Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional, non-Herlitz type, 226650 (includes enamel pitting); Amelogenesis Imperfecta; non-Herlitz junctional epidermolysis bullosa (nH-JEB) and amelogenesis imperfecta; hypoplastic amelogenesis imperfecta to Epidermolysis bullosa, junctional 4, intermediate, OMIM:619787 (includes enamel pitting); Hypoplastic amelogenesis imperfecta
Epidermolysis bullosa v1.9 COL17A1 Arina Puzriakova Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional, non-Herlitz type, 226650; Junctional Epidermolysis Bullosa; Generalised intermediate junctional Epidermolysis bullosa to Epidermolysis bullosa, junctional 4, intermediate, OMIM:619787
Epidermolysis bullosa and congenital skin fragility v1.51 COL17A1 Arina Puzriakova Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional, localisata variant, OMIM:226650; Epidermolysis bullosa, junctional, non-Herlitz type, OMIM:226650 to Epidermolysis bullosa, junctional 4, intermediate, OMIM:619787
Paediatric motor neuronopathies v1.78 SETX Sarah Leigh Publications for gene: SETX were set to 15106121
Childhood onset dystonia, chorea or related movement disorder v1.232 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487 to Spastic ataxia 5, autosomal recessive, OMIM:614487
Likely inborn error of metabolism v2.247 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Undiagnosed metabolic disorders v1.529 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Spinocerebellar ataxia 28, 610246; Ataxia, spastic, 5, autosomal recessive, 614487 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Possible mitochondrial disorder - nuclear genes v1.76 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Progressive external ophthalmoplegia with mitochondrial DNA deletions to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Primary immunodeficiency or monogenic inflammatory bowel disease v2.542 FASLG Eleanor Williams commented on gene: FASLG: Checking the mode of inheritance for this gene because in OMIM it is associated with Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859 with an autosomal dominant inheritance pattern listed (page last updated in 2014). Note the FASLG gene has previously been known as TNFSF6 and FASL). The FAS gene has previously been know as TNFRSF6.

Patients with homozygous variants:

PMID: 16627752 - Del-Rey et al 2006 - describe a Spanish patient with an ALPS phenotype and with a homozygous missense variant in FASL (A247E). The healthy mother was heterozygous for the variant. DNA from the father was not available.

PMID: 22857792 - Magerus-Chatinet et al 2013 - patient with a a severe form of ALPS who was found to have a homozygous 1-bp deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation.

PMID:25451160 - Nabhani et al 2014 - 2 siblings from a consanguineous Libyan family who presented with a severe phenotype of autoimmune lymphoproliferative syndrome (ALPS) were found by Sanger sequencing of FASLG to have a homozygous 1 bp insertion predicted to result in a frameshift and a truncated protein (p.P69Afs*75). The healthy mother was heterozygous for the variant.

Patients with heterozygous variants:

PMID: 8787672 - Wu et al 1996 - in a 64 year old African American male patient with systemic lupus erythematosus with lymphadenopathy they identified a heterozygous 84bp deletion within exon 4 of FASLG that results in a in-frame deletion using single stranded conformational polymorphism (SSCP).. The found decreased FasL activity in PBMC , decreased activation-induced cell death, and increased T cell proliferation after activation.

PMID: 17605793 - Bi et al 2007 - report an ALPS Type 1b white male patient with a heterozygous A530G mutation in the FasL gene. This variant was also found in his father and paternal grandmother. The father had lymphadenopathy as an adolescent but has been healthy otherwise except for psoriatic arthritis. The grandmother is not reported to have symptoms of ALPS. They show that the variant results in a dominant-interfering FasL protein that binds to the wild-type FasL protein and prevented it from effectively inducing apoptosis.

Other publications linked to this gene by the Human Phenotype Ontology Immune Mediated Disorders Consortium refer more to the phenotype of ALPS and not to FASLG variants specifically (PubMed IDs: 26907631, 16537120, 8806292, 22983577, 16394653).
Childhood onset dystonia, chorea or related movement disorder v1.231 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive 614487; Spinocerebellar ataxia 28 610246 to Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Adult onset dystonia, chorea or related movement disorder v1.170 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Hereditary ataxia with onset in adulthood v2.158 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Mitochondrial disorders v2.101 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Intellectual disability v3.1559 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Mitochondrial DNA maintenance disorder v1.9 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Progressive external ophthalmoplegia with mitochondrial DNA deletions to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Hereditary ataxia v1.302 SETX Sarah Leigh Phenotypes for gene: SETX were changed from ataxia with oculomotor apraxia type 2 (AOA2), juvenile amyotrophic lateral sclerosis (ALS4) and autosomal dominant ataxia; Ataxia-ocular apraxia-2 to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, OMIM:606002
Hereditary ataxia v1.301 SETX Sarah Leigh reviewed gene: SETX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.157 SETX Sarah Leigh Phenotypes for gene: SETX were changed from ataxia with oculomotor apraxia type 2 (AOA2), juvenile amyotrophic lateral sclerosis (ALS4) and autosomal dominant ataxia; Autosomal recessive spinocerebellar ataxia type 1, 606002; Ataxia-ocular apraxia-2 to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, OMIM:606002
Ataxia and cerebellar anomalies - narrow panel v2.295 SETX Sarah Leigh Phenotypes for gene: SETX were changed from Ataxia-ocular apraxia-2; ataxia with oculomotor apraxia type 2 (AOA2), juvenile amyotrophic lateral sclerosis (ALS4) and autosomal dominant ataxia to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, OMIM:606002
Ataxia and cerebellar anomalies - narrow panel v2.294 SETX Sarah Leigh reviewed gene: SETX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.156 SETX Sarah Leigh reviewed gene: SETX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amyotrophic lateral sclerosis/motor neuron disease v1.58 SETX Sarah Leigh edited their review of gene: SETX: Added comment: The Q2_22_MOI tag has been added to this gene as the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002 is also relevant to this panel.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.301 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spinocerebellar ataxia 28; Ataxia, spastic, 5, autosomal recessive; Spinocerebellar Ataxia, Dominant to Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Ataxia and cerebellar anomalies - narrow panel v2.294 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spinocerebellar ataxia 28; Spinocerebellar Ataxia, Dominant; Ataxia, spastic, 5, autosomal recessive to Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Amyotrophic lateral sclerosis/motor neuron disease v1.58 SETX Sarah Leigh Tag Q2_22_MOI tag was added to gene: SETX.
Amyotrophic lateral sclerosis/motor neuron disease v1.58 SETX Sarah Leigh Phenotypes for gene: SETX were changed from Amyotrophic lateral sclerosis 4, juvenile 602433 to Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, OMIM:606002
Amyotrophic lateral sclerosis/motor neuron disease v1.57 SETX Sarah Leigh Added comment: Comment on publications: PMID: 23881933 (putative disease causing variants reported in Table 1)
Amyotrophic lateral sclerosis/motor neuron disease v1.57 SETX Sarah Leigh Publications for gene: SETX were set to 22577233; 23129421; 23881933 (putative disease causing variants reported in Table 1).
Adult onset hereditary spastic paraplegia v1.102 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Spastic ataxia 5, autosomal recessive, OMIM:614487
Retinal disorders v2.258 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Optic atrophy 12, OMIM:618977, MONDO:0033549 to Optic atrophy 12, OMIM:618977, MONDO:0033549; Spastic ataxia 5, autosomal recessive, OMIM:614487
Retinal disorders v2.257 AFG3L2 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS review. Two families have been reported (PMID: 32219868) with recessive disease including optic atrophy associated with hearing loss, intellectual disability and ataxia, among others. This was considered sufficient to rate as green under AD/AR inheritance on the Optic neuropathy (R41) panel and therefore this MOI should also be reflected on the Retinal disorders panel.
Retinal disorders v2.257 AFG3L2 Arina Puzriakova Mode of inheritance for gene: AFG3L2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.256 AFG3L2 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: AFG3L2.
Optic neuropathy v2.68 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Optic atrophy 12, 618977 to Optic atrophy 12, OMIM:618977 (AD); Spastic ataxia 5, autosomal recessive, OMIM:614487 (AR)
Albinism or congenital nystagmus v1.23 SETX Sarah Leigh changed review comment from: The Q2_22_MOI tag has been added to this gene as the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal, as Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002 is relevant phenotype for this panel.; to: The Q2_22_MOI tag has been added to this gene as the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal, as Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002 is the relevant phenotype for this panel.
Albinism or congenital nystagmus v1.23 SETX Sarah Leigh edited their review of gene: SETX: Added comment: The Q2_22_MOI tag has been added to this gene as the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal, as Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002 is relevant phenotype for this panel.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.23 SETX Sarah Leigh Tag Q2_22_MOI tag was added to gene: SETX.
Albinism or congenital nystagmus v1.23 SETX Sarah Leigh Added comment: Comment on phenotypes: SETX are also associated with Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433, but this phenotype is not relevant to the Albinism or congenital nystagmus panel
Albinism or congenital nystagmus v1.23 SETX Sarah Leigh Phenotypes for gene: SETX were changed from Amyotrophic lateral sclerosis 4, juvenile 602433 AD; Spinocerebellar ataxia, autosomal recessive 1 606002 AR to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002
Early onset or syndromic epilepsy v2.517 SLC1A2 Sarah Leigh changed review comment from: PMID 28915517 reports one case of hmz c.1421+1G>C in a case of epileptic seizures and visual impairment. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function. In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other.; to: PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function. In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other.
Early onset or syndromic epilepsy v2.517 SLC1A2 Sarah Leigh reviewed gene: SLC1A2: Rating: ; Mode of pathogenicity: None; Publications: 23934111, 27476654; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.256 PRPF6 Zornitza Stark reviewed gene: PRPF6: Rating: AMBER; Mode of pathogenicity: None; Publications: 21549338, 32335390; Phenotypes: Retinitis pigmentosa 60, MIM# 613983; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1558 PRSS12 Zornitza Stark reviewed gene: PRSS12: Rating: AMBER; Mode of pathogenicity: None; Publications: 12459588; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1558 SLC35B2 Konstantinos Varvagiannis gene: SLC35B2 was added
gene: SLC35B2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid
Penetrance for gene: SLC35B2 were set to Complete
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 unrelated individuals with biallelic SLC35B2 variants have been reported. DD and ID were part of the phenotype.

There is currently no associated phenotype in OMIM/G2P/SysID. The gene has amber rating in the leukodystrophies panel of PanelApp Australia.

Consider inclusion in the current panel (or other possibly relevant ones eg. for skeletal disorders, short stature, white matter disorders, corpus callosum, etc) with amber rating.

---

Guasto et al (2022 - PMID:35325049) report 2 unrelated individuals with biallelic SLC35B2 variants.

SLC35B2 encodes solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporter), member B2.

The protein is located in the Golgi membrane and serves as transporter of the activated nucleotide sulfate PAPS from the cytosol, where it is synthesized to the Golgi lumen. Another PAPS transporter is encoded by SLC35B3. In the Golgi apparatus PAPS serves as substrate of sulfotransferases for the addition sulfate to the covalently attached GAG chains of proteoglycans (PGs).

The phenotype corresponded to a chondrodysplasia manifesting as severe pre- and postnatal growth retardation (height <-4 SD and -8 SD), early scoliosis, multiple joint dislocations (in one). There was severe DD affecting motor and expressive language development with associated ID. Brain imaging was suggestive of hypomyelinating leukodystrophy with thin corpus callosum and cerebral atrophy. One individual had a cleft palate in the context of Pierre Robin sequence.

Both individuals were investigated with exome sequencing.

The first individual - born to consanguineous parents - was homozygous for an in-frame del (NM_178148.3:c.1218_1220del, p.Leu407del) with Sanger sequencing confirming the variants, and heterozygosity in parents and 2 unaffected sibs. There was an initially identified hmz CUL7 variant (for 3M syndrome), which was not felt sufficient to explain the severity of the phenotype and notably ID.

The 2nd proband was homozygous for a fs variant (c.1224_1225delAG / p.Arg408SerfsTer18 - leading to loss of the last 8 amino acids) occurring in the context of uniparental isodisomy [iUPD(6)] spanning the complete chr6 based on the exome data.

Among the evidence presented for SLC35B2 and the variants :
- SLC35B2 has high mRNA expression in fetal and adult mouse brain and other tissues.
- Upon qPCR analysis of mRNA expression in human brain samples, the gene had expression across the brain (frontal lobe grey matter, subcortical frontal white matter/cerebellum).
- High expression was shown upon analysis of mouse brain single cell RNA data (EMBL) in oligodendrocytes and microglial cells.
- RT-PCR on mRNA from skin fibroblasts (both individuals) revealed significant decrease of SCL35B2 mRNA levels compared to controls.
- Transfection of C-terminal c-myc tagged wt or mutant proteins in HEK293F cells, followed by western blotting did not reveal significant difference at the protein level. Wt SLC35B2 localized at the Golgi apparatus as suggested by colocalization with GM130 marker. The 2 variants however displayed only partial colocalization (/loss of localization specificity) with diffuse signal in the cell.
- Chondroitin sulfate disaccharide sulfation was decreased upon HPLC disaccharide analysis in patient fibroblasts and bikunin (a circulating proteoglycan in blood) electrophoretic pattern in patient sera.
- Disorders due to variants in genes implicated in proteoglycan biogenesis (e.g. XYLT1, B3GALT6, CHSY1) are associated with skeletal/connective tissue manifestations with DD/ID.
- C-elegans model lacking pst-1 (SLC35B2 ortholog) provides support that the protein is required for migration, axonal guidance, and presynaptic development in a subset of neurons.
- dsm-1 - the rat ortholog - is expressed in rat brain in D-serine and NMDA receptor rich regions. When expressed in Xenopus oocytes it accelerated the efflux of D-serine (a co-agonist for NMDA receptor).
- Variants in other members of SLC superfamily (e.g. SLC17A5, SLC35A3, SLC29A3, SLC35A2) have been associated with brain-bone phenotypes.
Sources: Literature
Pulmonary arterial hypertension v2.21 EIF2AK4 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as BOTH mono and biallelic although OMIM just has autosomal recessive because there is a report of a heterozygous variant in this gene in a patient with pulmonary veno-occlusive disease.
Pulmonary arterial hypertension v2.21 EIF2AK4 Eleanor Williams Mode of inheritance for gene: EIF2AK4 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pulmonary arterial hypertension v2.20 EIF2AK4 Eleanor Williams Phenotypes for gene: EIF2AK4 were changed from Pulmonary venoocclusive disease 2, 234810; PVOD; pulmonary capillary hemangiomatosis; PCH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension; Idiopathic pulmonary arterial hypertension; IPAH to Pulmonary venoocclusive disease 2, OMIM:234810; PVOD; pulmonary capillary hemangiomatosis; PCH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension; Idiopathic pulmonary arterial hypertension; IPAH
Pulmonary arterial hypertension v2.19 EIF2AK4 Eleanor Williams Publications for gene: EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113; 26387786; 27884767; 27694411; 28087361; 28087362; 28972005; 29844075
Pulmonary arterial hypertension v2.18 EIF2AK4 Eleanor Williams reviewed gene: EIF2AK4: Rating: ; Mode of pathogenicity: None; Publications: 24292273, 24135949, 27809840, 32631303; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v1.16 DSC3 Eleanor Williams Phenotypes for gene: DSC3 were changed from Desmosomal disorders; Palmoplantar keratoderma, woolly hair to Desmosomal disorders; Palmoplantar keratoderma, woolly hair; Hypotrichosis and recurrent skin vesicles, OMIM:613102; hereditary hypotrichosis with recurrent skin vesicles, MONDO:0013136
Palmoplantar keratodermas v1.15 DSC3 Eleanor Williams Publications for gene: DSC3 were set to
Palmoplantar keratodermas v1.14 DSC3 Eleanor Williams changed review comment from: In OMIM this gene is associated with Hypotrichosis and recurrent skin vesicles (OMIM:613102) with a autosomal recessive mode of inheritance.

Two cases reported, both with homozygous variants in the affected individuals.

PMID: 19765682 - Ayub et al 2009 - large consanguineous family from Afghanistan with 4 affected siblings with hypotrichosis and the appearance of recurrent skin vesicle formation. Sequence analysis following homozygosity mapping identified a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in DSC3.

PMID: 31790667 - Onoufriadis et al 2020 - boy from consanguineous Egyptian family with skin blistering and hypotrichosis. A homozygous nonsense mutation in DSC3 (c.2180T>G; p.Leu727*) was identified. The parents and unaffected sister were heterozygous for this variant.; to: In OMIM this gene is associated with Hypotrichosis and recurrent skin vesicles (OMIM:613102) with a autosomal recessive mode of inheritance.

Two cases reported, both with homozygous variants in the affected individuals.

PMID: 19765682 - Ayub et al 2009 - large consanguineous family from Afghanistan with 4 affected siblings with hypotrichosis and the appearance of recurrent skin vesicle formation. Sequence analysis following homozygosity mapping identified a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in DSC3.

PMID: 31790667 - Onoufriadis et al 2020 - boy from consanguineous Egyptian family with skin blistering and hypotrichosis. A homozygous nonsense mutation in DSC3 (c.2180T>G; p.Leu727*) was identified. The parents and unaffected sister were heterozygous for this variant.

PMID: 18682494 - Chen et al 2008 - mouse model shows that loss of Dsc3 function in the epidermis causes impaired cell-cell adhesion, leading to intra-epidermal blistering and telogen hair loss.
Palmoplantar keratodermas v1.14 DSC3 Eleanor Williams Added comment: Comment on mode of inheritance: Only cases with homozygous variants have been reported, therefore it is recommended that the mode of inheritance is changed to Biallelic only following GMS review.
Palmoplantar keratodermas v1.14 DSC3 Eleanor Williams Mode of inheritance for gene: DSC3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.13 DSC3 Eleanor Williams Tag Q2_22_MOI tag was added to gene: DSC3.
Palmoplantar keratodermas v1.13 DSC3 Eleanor Williams commented on gene: DSC3
Intellectual disability v3.1558 CACNA2D1 Sarah Leigh Publications for gene: CACNA2D1 were set to 35293990; 28097321
Intellectual disability v3.1557 CACNA2D1 Sarah Leigh Tag Q2_22_rating tag was added to gene: CACNA2D1.
Intellectual disability v3.1557 CACNA2D1 Sarah Leigh Classified gene: CACNA2D1 as Amber List (moderate evidence)
Intellectual disability v3.1557 CACNA2D1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1557 CACNA2D1 Sarah Leigh Gene: cacna2d1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1556 CACNA2D1 Sarah Leigh reviewed gene: CACNA2D1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.517 CACNA2D1 Sarah Leigh reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.517 CACNA2D1 Sarah Leigh Classified gene: CACNA2D1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.517 CACNA2D1 Sarah Leigh Gene: cacna2d1 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.47 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is associated with 4 Osteogenesis imperfecta phenotypes, all of which are listed with an autosomal dominant mode of inheritance.

The gene is associated with Ehlers-Danlos syndrome, cardiac valvular type with a autosomal recessive mode of inheritance but this does not appear to affect the bones.

Therefore, monoallelic is the appropriate mode of inheritance for this gene on this panel.
Osteogenesis imperfecta v2.47 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.516 CACNA2D1 Sarah Leigh Publications for gene: CACNA2D1 were set to 35293990
Early onset or syndromic epilepsy v2.515 KCNC2 Sarah Leigh Classified gene: KCNC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.515 KCNC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.515 KCNC2 Sarah Leigh Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.514 KCNC2 Sarah Leigh Tag Q2_22_rating tag was added to gene: KCNC2.
Early onset or syndromic epilepsy v2.514 KCNC2 Sarah Leigh reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1556 FBXW7 Konstantinos Varvagiannis gene: FBXW7 was added
gene: FBXW7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW7 were set to 33057194; 35395208; 30885698; 26482194; 19963109; 20332316
Phenotypes for gene: FBXW7 were set to Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate
Penetrance for gene: FBXW7 were set to unknown
Review for gene: FBXW7 was set to AMBER
Added comment: While Kaplanis et al (2020 - Ref1), identified FBXW7 among 285 genes significantly associated with developmental disorders, a recent study by Stephenson et al (2022 - Ref2) describes the neurodevelopmental phenotype of 35 individuals making this gene relevant to the current panel. There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition although a neurodevelopmental phenotype was not reported in most cases.

There is currently no FBXW7-related phenotype in OMIM.

The gene is included in the DD panel of G2P [associated with: FBXW7-related developmental disorder (monoallelic), confidence: definitive, citing the study by Kaplanis et al]. SysID lists FBXW7 among the candidate ID genes (same Ref.). The gene has a green rating for ID in PanelApp Australia (VCGS participating in the recent publication).

Consider inclusion with amber/green rating. Also consider inclusion in other panels that may be relevant(macro/microcephaly, seizures, CHD, corpus callosum / cerebellar abnormalities, cleft palate, WT, etc).

[1]------------
Kaplanis et al (2020 - PMID: 33057194), by combining exome data from 31,058 parent offspring trios from the DDD study, Radboudumc and GeneDx, identified 285 genes significantly associated with developmental disorders, 28 of which (incl. FBXW7) not previously robustly associated with these disorders.

[2]------------
Stephenson et al (2022 - PMID: 35395208) provide clinical information on 35 individuals harboring germline monoallelic FBXW7 variants or chromosomal deletions spanning this gene.

The phenotype corresponded to a phenotypically variable NDD characterized by hypotonia (in about 2/3), neurodevelopmental abnormality (34/35 - as discussed later), seizures (8/35), abnormal brain morphology (13/17 - in 7/17 abnormal CC, in 5/17 abn. cerebellum, etc), head circumference (macrocephaly in 10/35, microcephaly in 2/35). Additional features included abnormal palate or uvula morphology (10/35 - cleft palate in 3 from 2 families while 1 individual from a 3rd family had bifid uvula) or abnormal heart morphology (11/35), ophthalmologic features (e.g. strabismus in 5/35) or hearing impairment (2/35). There was no recognizable gestalt (deeply set eyes with upper eyelid fullness in 9/35).

As for the DD/ID this ranged from borderline to severe, characterized as mild-moderate in 27/35, severe in 3/35. One individual did not present neurodevelopmental abnormality 1/35.

FBXW7 encodes F-box and WD40 domain protein 7 which is part of the SCF E3 ligase complex (SKP1/CUL1/F-box protein) exerting a role of recognition and binding of target proteins for degradation by the ubiquitin proteasome system. In this way FBWX7 participates in regulating a network of proteins involved in cell division, growth, differentiation (as summarized by Roversi et al - Ref2).

Most individuals were investigated by trio-WES/WGS (few with singleton WES or CMA only). 28 germline FBXW7 variants were identified incl. missense (N=21), pLoF (predicted or not to undergo NMD) and 2 deletions encompassing but not limited to FBXW7.

Additional SNVs/CNVs (e.g. an inh intragenic DPP6 dup in one individual (#9) with deletion, other de novo 4q CNVs (#10), an inh 22q spanning partially an ISCA TS region, a CACNA1A and KMT2D SNV, etc) were reported in few individuals.

Most variants arose dn (N=30) with two individuals displaying mosaicism (2/30) and three individuals having inherited the variant from their affected parent. CNVs had occurred dn.

3 missense SNVs were recurrent in unrelated individuals.

All variants identified affected all FBXW7 isoforms.

As the authors comment missense variants clustered at the C-terminal half of the protein with most (16/21) occurring within the WD40 domain. [The N-terminal part commented in the literature to affect localization].

The crystal structure of FBXW7 and SKP1 complex has been determined with CYCLIN E1/DISC1 as substrates, and in silico modeling revealed that all missense variants aligned with residues required for this interaction, or adjacent ones.

All were absent from gnomAD, while missense variants from gnomAD (N=78) were not predicted have significant effect on the binding affinity.

Variant studies revealed that most missense variants (6/7 tested - Arg689Gln being the exception) are unlikely to cause protein instability or degradation in vivo.

Co-expression of these missense variants with CYCLIN E1 / E2, known FBXW7 substrates revealed that variants were less efficient at degrading the substrate with variants in the WD40 domain having greater impact (in some cases E1 / E2 - specific).

Elav-Gal4 mediated neuronal knockdown of the Drosophila ortholog archipelago (ago) using 2 RNAi-s with different efficiency was shown to affect learning or compromise neuronal function (also related to the level of knockdown).

The authors summarize results from animal models for the role of this gene in development and the nervous system.

KO mice die in utero at E10.5 manifesting abn. of hematopoietic or vascular development and heart-chamber maturation(*). Some htz knock-in for human cancer variants, display perinatal lethality, abn lung, cleft palate (30%)(*),etc. Conditional gut specific deletion results in impaired differentiation of intestinal goblet cells (*)(constipation in 16/35 in cohort). KO limited to CNS and PNS results in defective sucking and morphological brain abnormalities. Haploinsufficiency in the nervous system was associated with impaired differentiation of neural stem cells (possibly through a Notch-mediated mechanism). KO in Schwann cells of the peripheral nervous system resulted in enhanced myelination.

Excessive oligodendrocyte cells and hypermyelination (as a result of elevated Notch & mTOR signaling) are observed in homozygous mutant zebrafish or after morpholino-mediated fbxw7 knockdown.

Overall, the authors propose haploinsufficiency or loss-of-function as the underlying mechanism.

Finally, as the authors comment, FBXW7 is a tumor suppressor among the most commonly mutated genes in human cancer (3.5%). Germline variants have been previously reported in individuals with cancer (Wilms tumor, rhabdoid, etc - most summarized below). However, none of the 35 individuals in this cohort (oldest 44 y.o.) had any history of cancer.

Reports of individuals with germline variants causing (monoallelic) disruption of FBXW7 - cases without DD/ID:

[3]------------
Mahamdallie et al (2019 - PMID: 30885698) investigated with WES a cohort of 890 individuals with Wilms tumor (799 non-familial disease, 91 from WT pedigrees). In this context they identified 4 individuals having developed WT (ages: 28-76m) with FBXW7 dn or inherited LoF variants (710G>A / p.Trp237* dn - 1972C>T / p.Arg658* - inh:NA, 1017_1021del5, 670C>T - paternal / p.Arg224* inh:NA - RefSeq not provided). One additional individual with a missense variant (1753A>T / p.Ser585Cys - dn) had developed rhabdoid tumor. While the authors mentioned additional features for other subjects in their cohort, among the 5 individuals with FBXW7 variants, only one had hypotonia (ID_0592) and another (ID_7520) had two febrile convulsions.

[4]------------
Roversi et al (2015 - PMID: 26482194) described the phenotype of a 34 y.o. female with syndromic presentation (macrocephaly, nephrotic syndrome due to FSGS, Hodgkin's lymphoma, Wilms tumor, ovarian cystadenoma, breast carcinoma) harboring a 157 kb deletion of 4q31.3.

Eventual DD/ID was not reported despite detailed clinical description.

The deletion spanned almost the entire FBXW7 gene and a pseudogene (hg19 - chr4:153205202-153362047). The authors provided evidence that the del affected the maternal allele as dn event (maternal mosaicism excluded). Expression of FBXW7 in patient-derived EBV lymphoblastoid cell line revealed decreased levels of expression compared to controls. At somatic level, the authors looked for eventual 2nd hit in tumor tissue (which was not the case) while they demonstrated decreased FBXW7 expression in a WT sample compared to normal renal tissue. Previously, variants in other genes candidate for the phenotype were ruled out (Sanger & MLPA for TP53, BRCA1/2, PALB2, WT1, 11p15 MS-MLPA, std karyotype).

[5]------------
Kuiper et al (2015 - PMID: 19963109), in a 58 y.o. patient with recurrence of RCC, identified a constitutional translocation [t(3;4)(q21;q31)]. Using long-range PCR they defined the breakpoints at 3q21.3 (128379059 - hg18) between the PLXNA1 and C3orf56 genes while the chr4 breakpoint was located within the second intron of FBXW7 (pos. 153500813 - hg18). There were no additional phenotypes reported.

[6]------------
Williams et al (2010 - PMID: 20332316) reported a patient with WT harboring germline variants in WT1 and FBXW7. While the phenotype was sufficiently explained by a germline stopgain WT1 variant with a frameshift WT1 variant (as 2nd hit) confined to the tumor, the authors identified a germline in-frame FBXW7 insertion in the same individual (c.45_46insCCT / p.Thr15_Gly16insPro - RefS : NA) [if correct corresponding to: https://gnomad.broadinstitute.org/variant/4-153332910-C-CAGG - 345/281696 alleles in gnomAD].
Sources: Literature
Early onset or syndromic epilepsy v2.514 KCNC2 Sarah Leigh Publications for gene: KCNC2 were set to 32392612; 31972370
Intellectual disability v3.1556 DTYMK Sarah Leigh Classified gene: DTYMK as Amber List (moderate evidence)
Intellectual disability v3.1556 DTYMK Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1556 DTYMK Sarah Leigh Gene: dtymk has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1555 DTYMK Sarah Leigh Tag Q2_22_rating tag was added to gene: DTYMK.
Intellectual disability v3.1555 DTYMK Sarah Leigh reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1555 DTYMK Sarah Leigh Phenotypes for gene: DTYMK were changed from 31271740; 34918187; 35346037 to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Intellectual disability v3.1554 DTYMK Sarah Leigh Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Early onset or syndromic epilepsy v2.513 DTYMK Sarah Leigh Classified gene: DTYMK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.513 DTYMK Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be made green at the next major review.
Early onset or syndromic epilepsy v2.513 DTYMK Sarah Leigh Gene: dtymk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.512 DTYMK Sarah Leigh Tag Q2_22_rating tag was added to gene: DTYMK.
Fetal anomalies v1.858 COL1A2 Eleanor Williams changed review comment from: The mode of inheritance for the following phenotypes is monoallelic.
- Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 (OMIM:619120)
- Ehlers-Danlos syndrome, arthrochalasia type, 2 (OMIM:617821)
- Osteogenesis imperfecta, type II (OMIM:166210)
- Osteogenesis imperfecta, type III (OMIM:259420)
- Osteogenesis imperfecta, type IV (OMIM:166220)

Only Ehlers-Danlos syndrome, cardiac valvular type (OMIM: 225320) has a biallelic mode of inheritance.; to: Variants in this gene are associated with the following phenotypes in OMIM with a monoallelic mode of inheritance:
- Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 (OMIM:619120)
- Ehlers-Danlos syndrome, arthrochalasia type, 2 (OMIM:617821)
- Osteogenesis imperfecta, type II (OMIM:166210)
- Osteogenesis imperfecta, type III (OMIM:259420)
- Osteogenesis imperfecta, type IV (OMIM:166220)

Only Ehlers-Danlos syndrome, cardiac valvular type (OMIM: 225320) has a biallelic mode of inheritance.
Fetal anomalies v1.858 COL1A2 Eleanor Williams commented on gene: COL1A2
Early onset or syndromic epilepsy v2.512 DTYMK Sarah Leigh reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.858 MSX1 Arina Puzriakova Phenotypes for gene: MSX1 were changed from CLEFT LIP +/- CLEFT PALATE to Orofacial cleft 5, OMIM:608874
Clefting v2.67 MSX1 Arina Puzriakova Phenotypes for gene: MSX1 were changed from Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600; CLP with dental anomalies; Cleft lip to Orofacial cleft 5, OMIM:608874; Tooth agenesis, selective, 1, with or without orofacial cleft, OMIM:106600
Intellectual disability v3.1553 MSX1 Arina Puzriakova Phenotypes for gene: MSX1 were changed from Tooth agenesis, selective, 1, with or without orofacial cleft, 106600; Orofacial cleft 5, 608874; Ectodermal dysplasia 3, Witkop type, 189500 to Ectodermal dysplasia 3, Witkop type, OMIM:189500; Orofacial cleft 5, OMIM:608874; Tooth agenesis, selective, 1, with or without orofacial cleft, OMIM:106600
Ectodermal dysplasia without a known gene mutation v1.23 MSX1 Arina Puzriakova Phenotypes for gene: MSX1 were changed from Ectodermal dysplasia 3, Witkop type 189500 to Ectodermal dysplasia 3, Witkop type, OMIM:189500
Ectodermal dysplasia v1.41 MSX1 Arina Puzriakova Phenotypes for gene: MSX1 were changed from Ectodermal dysplasia 3, Witkop type 189500 to Ectodermal dysplasia 3, Witkop type, OMIM:189500
Ehlers Danlos syndrome with a likely monogenic cause v2.65 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: The mode of inheritance for Ehlers-Danlos syndrome, arthrochalasia type, 2, OMIM:617821 is monoallelic, but for Ehlers-Danlos syndrome, cardiac valvular type, OMIM:225320 it is biallelic, so it is correct that the mode of inheritance on this panel is BOTH mono- and bi-allelic.
Ehlers Danlos syndrome with a likely monogenic cause v2.65 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.205 COL1A2 Eleanor Williams Phenotypes for gene: COL1A2 were changed from Ehlers-Danlos syndrome, cardiac valvular form 225320; Ehlers-Danlos syndrome, type VIIB 130060; Osteogenesis imperfecta, type II 166210; Osteogenesis imperfecta, type III 259420; Osteogenesis imperfecta, type IV 166220 to Ehlers-Danlos syndrome, cardiac valvular form, OMIM:225320; Ehlers-Danlos syndrome, type VIIB, OMIM:130060; Osteogenesis imperfecta, type II, OMIM:166210; Osteogenesis imperfecta, type III, OMIM:259420; Osteogenesis imperfecta, type IV, OMIM:166220
Skeletal dysplasia v2.204 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic for now, but adding a tag for GMS review. Only Ehlers-Danlos syndrome, cardiac valvular type is biallelic, and this phenotype may not be within scope of the Skeletal dysplasia panel.
Skeletal dysplasia v2.204 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1552 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from Acrocapitofemoral dysplasia, 607778; Brachydactyly, type A1, 112500 to Acrocapitofemoral dysplasia, OMIM:607778; Brachydactyly, type A1, OMIM:112500
Fetal anomalies v1.857 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from BRACHYDACTYLY, TYPE A1; ACROCAPITOFEMORAL DYSPLASIA to Acrocapitofemoral dysplasia, OMIM:607778; Brachydactyly, type A1, OMIM:112500
Skeletal dysplasia v2.203 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from Acrocapitofemoral dysplasia 607778; Brachydactyly, type A1 112500 to Acrocapitofemoral dysplasia, OMIM:607778; Brachydactyly, type A1, OMIM:112500
Limb disorders v2.78 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from Acrocapitofemoral dysplasia 607778; Brachydactyly, type A1 112500; syndactyly and craniosynostosis; F syndrome to Acrocapitofemoral dysplasia, OMIM:607778; Brachydactyly, type A1, OMIM:112500
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.75 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from 185900; chr2q35dup syndrome 185900; Acrocapitofermoral dysplasia 607778; bracydactyly type A1 112500 to Syndactyly, type 1, with or without craniosynostosis, OMIM:185900; Chr2q35dup syndrome
Skeletal dysplasia v2.202 COL1A2 Eleanor Williams Tag Q2_22_MOI tag was added to gene: COL1A2.
Tag Q2_22_expert_review tag was added to gene: COL1A2.
Skeletal dysplasia v2.202 DVL2 Eleanor Williams Classified gene: DVL2 as Amber List (moderate evidence)
Skeletal dysplasia v2.202 DVL2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for consideration for GREEN rating following GMS review. Although only 1 case has been reported, supporting evidence comes from canine data and from the fact that similar causative variants associated with Robinow syndrome have been found in the other two Dishevelled paralogs.
Skeletal dysplasia v2.202 DVL2 Eleanor Williams Gene: dvl2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.201 DVL2 Eleanor Williams Tag Q2_22_expert_review tag was added to gene: DVL2.
Skeletal dysplasia v2.201 DVL2 Eleanor Williams Publications for gene: DVL2 were set to PMID: 35047859
Skeletal dysplasia v2.200 DVL2 Eleanor Williams Tag Q2_21_NHS_review tag was added to gene: DVL2.
Tag Q2_22_rating tag was added to gene: DVL2.
Skeletal dysplasia v2.200 DVL2 Eleanor Williams reviewed gene: DVL2: Rating: ; Mode of pathogenicity: None; Publications: 35047859, 33599851, 30521570; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v2.200 DVL2 Eleanor Williams Phenotypes for gene: DVL2 were changed from autosomal dominant Robinow sydrome to autosomal dominant Robinow sydrome; Robinow syndrome, MONDO:0019978
Childhood onset dystonia, chorea or related movement disorder v1.230 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to
Childhood onset dystonia, chorea or related movement disorder v1.229 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280; Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Childhood onset dystonia, chorea or related movement disorder v1.228 HSPD1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: HSPD1.
Childhood onset dystonia, chorea or related movement disorder v1.228 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update. Biallelic variants cause a paediatric-onset leukodystrophy (MIM# 612233) which features motor disability associated progressive limb spasticity and contractures, and some patients have been found to have choreoatetotic movements (PMID: 18571143, 27405012). On the other hand, monoallelic variants are associated with a pure adult-onset HSP (SPG13, MIM# 605280) which is not pertinent to this panel.
Childhood onset dystonia, chorea or related movement disorder v1.228 HSPD1 Arina Puzriakova Mode of inheritance for gene: HSPD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Osteogenesis imperfecta v2.46 MBTPS2 Eleanor Williams Publications for gene: MBTPS2 were set to 27380894
Intellectual disability v3.1551 HSPD1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: HSPD1.
Intellectual disability v3.1551 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280Leukodystrophy, hypomyelinating, 4, 612233; SPASTIC PARAPLEGIA AUTOSOMAL DOMINANT TYPE 13 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Intellectual disability v3.1550 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to
Intellectual disability v3.1549 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update. Biallelic variants cause a paediatric-onset leukodystrophy (MIM# 612233) which can feature severe DD/ID in some cases (PMID: 18571143, 27405012), whereas monoallelic variants are associated with a pure adult-onset HSP (SPG13, MIM# 605280) which is not pertinent to this panel.
Intellectual disability v3.1549 HSPD1 Arina Puzriakova Mode of inheritance for gene: HSPD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb disorders v2.77 BMP2 Eleanor Williams commented on gene: BMP2: There is currently no ClinGen curated CNV covering this region on chromosome 20.
Skeletal dysplasia v2.199 BMP2 Eleanor Williams Tag cnv tag was added to gene: BMP2.
Skeletal dysplasia v2.199 BMP2 Eleanor Williams commented on gene: BMP2: There is currently no ClinGen curated CNV covering this region on chromosome 20.
Mitochondrial disorders v2.100 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280; Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233 (AR); Spastic paraplegia 13, autosomal dominant, OMIM:605280 (AD)
Early onset or syndromic epilepsy v2.512 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.74 NFIA Eleanor Williams Classified gene: NFIA as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.74 NFIA Eleanor Williams Gene: nfia has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v2.273 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant to Spastic paraplegia 13, autosomal dominant, OMIM:605280
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Tag Q2_22_rating tag was added to gene: NFIA.
Tag Q2_22_NHS_review tag was added to gene: NFIA.
Likely inborn error of metabolism v2.246 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Leukodystrophy, hypomyelinating, 4, 612233; Spastic paraplegia 13, autosomal dominant, 605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233 (AR); Spastic paraplegia 13, autosomal dominant, OMIM:605280 (AD)
Possible mitochondrial disorder - nuclear genes v1.75 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant 605280; Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233 (AR); Spastic paraplegia 13, autosomal dominant, OMIM:605280 (AD)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Classified gene: NFIA as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Added comment: Comment on list classification: As Expert reviewer notes, there are sufficient cases reported with a craniosynostosis phenotype and variants in this gene to promote it to green following GMS review.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Gene: nfia has been classified as Red List (Low Evidence).
Undiagnosed metabolic disorders v1.528 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spastic paraplegia 13, autosomal dominant, 605280; Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233 (AR); Spastic paraplegia 13, autosomal dominant, OMIM:605280 (AD)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.72 NFIA Eleanor Williams Phenotypes for gene: NFIA were changed from to Metopic synostosis, hydrocephalus, thin corpus callosum, mild developmental delay, autism, macrocephaly
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.71 NFIA Eleanor Williams Mode of inheritance for gene: NFIA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.70 NFIA Eleanor Williams Publications for gene: NFIA were set to
Adult onset hereditary spastic paraplegia v1.101 HSPD1 Arina Puzriakova Classified gene: HSPD1 as Amber List (moderate evidence)
Adult onset hereditary spastic paraplegia v1.101 HSPD1 Arina Puzriakova Added comment: Comment on list classification: The evidence for this gene-disease association is borderline as only 2 families have been reported to date with HSPD1-related AD adult-onset SPG which may be associated with variable penetrance. However, this phenotype is likely best represented by the R60 panel which may justify its inclusion to minimise risk of missing diagnoses - this will be flagged for GMS discussion to determine the most appropriate classification given the current evidence.
Adult onset hereditary spastic paraplegia v1.101 HSPD1 Arina Puzriakova Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia v1.295 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to Hansen et al. (2002)
Adult onset hereditary spastic paraplegia v1.100 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to 11898127
Skeletal dysplasia v2.199 PRKAR1A Eleanor Williams Added comment: Comment on mode of inheritance: No reports of biallelic cases found so recommendation is to change the mode of inheritance to monoallelic only after GMS review.
Skeletal dysplasia v2.199 PRKAR1A Eleanor Williams Mode of inheritance for gene: PRKAR1A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset hereditary spastic paraplegia v1.99 HSPD1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: HSPD1.
Tag Q2_22_expert_review tag was added to gene: HSPD1.
Adult onset hereditary spastic paraplegia v1.99 HSPD1 Arina Puzriakova reviewed gene: HSPD1: Rating: ; Mode of pathogenicity: None; Publications: 10677329, 11898127, 17420924; Phenotypes: Spastic paraplegia 13, autosomal dominant, OMIM:605280; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.198 PRKAR1A Eleanor Williams Phenotypes for gene: PRKAR1A were changed from Acrodysostosis 1, with or without hormone resistance 101800; Myxoma, intracardiac 255960; Pigmented nodular adrenocortical disease, primary, 1 610489 to Acrodysostosis 1, with or without hormone resistance, OMIM:101800
Skeletal dysplasia v2.197 PRKAR1A Eleanor Williams Publications for gene: PRKAR1A were set to
Skeletal dysplasia v2.196 PRKAR1A Eleanor Williams Mode of pathogenicity for gene: PRKAR1A was changed from to Other
Skeletal dysplasia v2.195 PRKAR1A Eleanor Williams Tag Q2_22_MOI tag was added to gene: PRKAR1A.
Skeletal dysplasia v2.195 PRKAR1A Eleanor Williams edited their review of gene: PRKAR1A: Added comment: Looking at the mode of inheritance of this gene on the Skeletal dysplasia panel where it is Both mono and bi-allelic.

In OMIM and Gene2Phenotype the relevant phenotypes of Acrodysostosis 1, with or without hormone resistance, OMIM:101800 and ACRODYSOSTOSIS respectively are listed with autosomal dominant/monoallelic inheritance.

There are several reports of heterozygous variants in PRKAR1A in patients with Acrodysostosis (PMIDs: 21651393, 22464250, 22464252, 28804209, 23425300, 25075981, 26763073). No reports of biallelic variants were found in a search of PubMed. Therefore the recommendation is for the mode of inheritance to be changed to monoallelic only.; Changed mode of pathogenicity: Other; Changed publications to: 21651393, 22464250, 22464252, 28804209, 23425300, 25075981, 26763073; Changed phenotypes to: Acrodysostosis 1, with or without hormone resistance, OMIM:101800; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v2.137 HSPD1 Arina Puzriakova Classified gene: HSPD1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.137 HSPD1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update under the AR inheritance pattern for the childhood-onset panel.
Childhood onset hereditary spastic paraplegia v2.137 HSPD1 Arina Puzriakova Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.136 HSPD1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: HSPD1.
Childhood onset hereditary spastic paraplegia v2.136 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to 17420924; 10677329; 11898127
Childhood onset hereditary spastic paraplegia v2.135 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed from 'monoallelic' to 'biallelic' as per the review by Zornitza Stark (Australian Genomics) stating that only biallelic variants cause a more severe phenotype including spasticity with onset in childhood.
Childhood onset hereditary spastic paraplegia v2.135 HSPD1 Arina Puzriakova Mode of inheritance for gene: HSPD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.134 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Adult onset hereditary spastic paraplegia v1.99 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, autosomal recessive, 612233; Spastic paraplegia 13, autosomal dominant or pseudoautosomal, NOT imprinted, 605280 to Spastic paraplegia 13, autosomal dominant, OMIM:605280
Adult onset hereditary spastic paraplegia v1.98 HSPD1 Arina Puzriakova Penetrance for gene HSPD1 was set from to None
Hereditary spastic paraplegia v1.294 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' only to 'both mono- and biallelic'. Biallelic variants cause a paediatric-onset leukodystrophy, with spasticity as a feature (MIM# 612233), while monoallelic variants have been associated with adult-onset HSP (MIM# 605280) - both phenotypes are relevant to this panel.
Hereditary spastic paraplegia v1.294 HSPD1 Arina Puzriakova Mode of inheritance for gene: HSPD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.293 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant to Leukodystrophy, hypomyelinating, 4, OMIM:612233 (AR); Spastic paraplegia 13, autosomal dominant, OMIM:605280 (AD)
Fetal anomalies v1.856 LIFR Eleanor Williams Phenotypes for gene: LIFR were changed from Stuve-Wiedemann syndrome; Schwartz-Jampel type 2 syndrome to Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, OMIM:601559
Skeletal dysplasia v2.195 LIFR Eleanor Williams Phenotypes for gene: LIFR were changed from Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome 601559 to Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, OMIM:601559
Fetal anomalies v1.855 LIFR Eleanor Williams Publications for gene: LIFR were set to
Fetal anomalies v1.854 LIFR Eleanor Williams changed review comment from: Heterozygous variants in LIFR are associated with a CAKUT phenotype, while homozygous variants are associated with skeletal Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndromes. At the moment the mode of inheritance for this gene on the Fetal anomalies panel is biallelic only.

GMS fetal group input is needed to decide whether the mode of inheritance for this gene should also include monoallelic cases as the renal phenotype might be detected antenatally e.g. hydronephrosis.; to: Heterozygous variants in LIFR are associated with a CAKUT phenotype, while homozygous variants are associated with skeletal Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndromes. At the moment the mode of inheritance for this gene on the Fetal anomalies panel is biallelic only.

GMS fetal group input is needed to decide whether the mode of inheritance for this gene should also include monoallelic cases as the renal phenotype might be detected antenatally e.g. hydronephrosis. The paper describing the CAKUT cases is PMID: 28334964 (Kosfeld et al 2017).
Distal myopathies v1.47 GIPC1 Arina Puzriakova Phenotypes for gene: GIPC1 were changed from Oculopharyngodistal myopathy-2 (OPDM2), MIM#618940 to Oculopharyngodistal myopathy 2, OMIM:618940
Distal myopathies v1.46 GIPC1 Arina Puzriakova Publications for gene: GIPC1 were set to 32413282
Arthrogryposis v3.159 KIF26B Arina Puzriakova Classified gene: KIF26B as Red List (low evidence)
Arthrogryposis v3.159 KIF26B Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single case (PMID: 30151950) has been reported to this date.
Arthrogryposis v3.159 KIF26B Arina Puzriakova Gene: kif26b has been classified as Red List (Low Evidence).
Fetal anomalies v1.854 LIFR Eleanor Williams commented on gene: LIFR
Fetal anomalies v1.854 LIFR Eleanor Williams Tag Q2_22_MOI tag was added to gene: LIFR.
Fetal anomalies v1.854 LIFR Eleanor Williams Tag Q2_22_expert_review tag was added to gene: LIFR.
Intellectual disability v3.1548 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Epidermolysis bullosa simplex, Ogna type, 131950; Epidermolysis bullosa simplex with pyloric atresia, 612138; Muscular dystrophy, limb-girdle, type 2Q, 613723 to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive, OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138; Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.38 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670
Congenital myaesthenic syndrome v2.40 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Congenital myasthenic syndrome; Plectin deficiency; Congenital myasthenic syndrome associatedwith epidermolysis bullosa (EBS) to Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670
Congenital muscular dystrophy v2.28 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Muscular dystrophy, limb-girdle autosomal recessive 17, 613723; Epidermolysis bullosa simplex with muscular dystrophy, 226670 to Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670
Familial cicatricial alopecia v1.4 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from PLEC-related Epidermolysis Bullosa; Epidermolysis bullosa simplex with pyloric atresia, 612138; Epidermolysis bullosa simplex with muscular dystrophy, 226670; Epidermolysis bullosa simplex, Ogna type, 131950; scarring alopecia to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive , OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138
Ectodermal dysplasia v1.40 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from PLEC-related Epidermolysis Bullosa; Epidermolysis bullosa simplex, Ogna type, 131950; scarring alopecia; Epidermolysis bullosa simplex with muscular dystrophy, 226670; Epidermolysis bullosa simplex with pyloric atresia, 612138 to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive , OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138
Epidermolysis bullosa v1.8 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Epidermolysis bullosa simplex, Ogna type (AD), 131950; Epidermolysis bullosa simplex including Ogna variant; Epidermolysis Bullosa Simplex, Ogna Type; Epidermolysis bullosa simplex with pyloric atresia (AR), 612138; Epidermolysis bullosa simplex with pyloric atresia; Epidermolysis Bullosa Simplex With Pyloric Atresia; Muscular dystrophy with epidermolysis bullosa simplex (AR), 226670; Epidermolysis Bullosa with Muscular Dystrophy; Epidermolysis Bullosa Simplex With Muscular Dystrophy to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive , OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams edited their review of gene: TTC21B: Added comment: Looking at the mode of inheritance for this gene. It is reported as both AD and AR in OMIM for Nephronophthisis 12, OMIM:613820.

There are many biallelic cases reported e.g.

PMID: 21258341 - Davis et al 2011 - report 5 families with isolated nephronophthisis (NPHP). Patients in 3 families had compound heterozygous variants (P209L/C552X, c.2758-2A>G/P209L, W150R/c.3264-3C>G) in TTC21B and 2 families with a milder phenotype were homozygous for the P209L variant. They observed the same haplotype at coding regions spanning the locus in all P209L homozygotes. In all 5 families individuals heterozygous for the variants were unaffected. They also report one case with compound het variants (R411X/L795P) with a syndromic Jeune Asphyxiating Thoracic Dystrophy phenotype.

PMID: 26940125 - Bullich et al 2017 - TTC21B variants and nephrotic proteinuria with FSGS and tubulointerstitial lesions were identified in 2 families with homozygous (p.P209L) variants (both families from Morocco, high blood pressure noted in individuals from each), and in 1 family with compound het variants (p.P209L and p.H426D)(family from Spain).

PMID:34957165 - Gambino et al 2021 - patient from a North African family with severe hypertension and chronic kidney disease at age 20. Several cases of hypertension, myopia, and severe kidney disease were reported in the extended family. A homozygous p.P209L variant was identified in TTC21B.

PMID:34805047 - Bezdíčka et al 2021 - 2.5 yo patient presenting with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis. She was hypertensive on admission. Compound het variants in TTC21B were identified p.Pro209Leu and p.Cys14Arg. The mother was a healthy carrier of the c.626C>T, p.Pro209Leu heterozygous variant.

PMID:35289079 - Olinger et al 2022 - 2 siblings with extreme early-onset HTN, proteinuria, and progressive CKD leading to kidney failure. Compound het variants in TTC21B were identified (p.(Gln834Ter) and p.(Pro209Leu)).

However, there are also reports of heterozygous variants in TTC21B in patients with kidney disease but it is thought that these may be modifier variants

PMID: 26940125 - Bullich et al 2017 - rare heterozygous variants in TTC21B were found in 5 patients, 4 with glomerular disease and 1 with cystic disease, but in addition to other likely pathogenic variants in other renal disease related genes (PKD1 , COL4A3, COL4A5 and NPHS2) suggesting a modifier role of TTC21B alleles. 2 patients presented a more severe phenotype than expected. A similar frequency for the total set of rare TTC21B variants predicted to be pathogenic was found between renal patients and controls

PMID: 21258341 - Davis et al 2011 - found an enrichment of pathogenic TTC21B alleles in ciliopathy patients (∼5%) and suggest that TTC21B might be a common contributor to the total mutational load in ciliopathies.; Changed publications to: 21258341, 26940125, 34957165, 34805047, 35289079
Intellectual disability v3.1547 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Dyskeratosis congenita, autosomal recessive 6, 616353 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353
Familial pulmonary fibrosis v1.29 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, 616371 to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Cytopenia - NOT Fanconi anaemia v1.64 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from 616371 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4; 616353 Dyskeratosis congenita, autosomal recessive 6; 616353 Dyskeratosis congenita, autosomal recessive 6 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Haematological malignancies cancer susceptibility v2.27 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Adult solid tumours cancer susceptibility v2.20 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from 616353 Dyskeratosis congenita, autosomal recessive 6; 616371 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Childhood solid tumours v2.33 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from 616353 Dyskeratosis congenita, autosomal recessive 6; 616371 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Haematological malignancies for rare disease v1.11 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams Tag Q2_22_MOI tag was added to gene: TTC21B.
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams Phenotypes for gene: TTC21B were changed from Short-rib thoracic dysplasia 4 with or without polydactyly, MIM 613819; Nephronopthisis 12 MIM 613820 to Nephronopthisis 12, OMIM:613820
Extreme early-onset hypertension v1.18 TTC21B Eleanor Williams Phenotypes for gene: TTC21B were changed from Hypertension; focal segmental glomerulosclerosis; nephronopthisis; myopia to Hypertension; focal segmental glomerulosclerosis; nephronopthisis; myopia; Nephronophthisis 12, OMIM:613820
Extreme early-onset hypertension v1.17 TTC21B Eleanor Williams Publications for gene: TTC21B were set to 24876116; 26940125; 34957165; 34805047
Extreme early-onset hypertension v1.16 TTC21B Eleanor Williams Classified gene: TTC21B as Green List (high evidence)
Extreme early-onset hypertension v1.16 TTC21B Eleanor Williams Added comment: Comment on list classification: Promoting this gene to green as there are sufficient cases in which hypertension is a characteristic of the disease phenotype.
Extreme early-onset hypertension v1.16 TTC21B Eleanor Williams Gene: ttc21b has been classified as Green List (High Evidence).
Extreme early-onset hypertension v1.15 TTC21B Eleanor Williams reviewed gene: TTC21B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.156 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Behr syndrome, 210000; Optic atrophy plus syndrome, 125250 to Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Optic neuropathy v2.67 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Optic neuropathy v2.66 OPA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update. Biallelic variants cause Behr syndrome (MIM# 210000) in which early-onset optic atrophy is a main clinical feature of the phenotype (PMID: 20157015; 21636302; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Optic neuropathy v2.66 OPA1 Arina Puzriakova Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Optic neuropathy v2.65 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Optic neuropathy v2.64 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1 165500; Optic atrophy plus syndrome 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Optic neuropathy v2.63 OPA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: OPA1.
Hereditary neuropathy v1.450 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Hereditary neuropathy or pain disorder v1.98 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Classified gene: OPA1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Added comment: Comment on list classification: It has now been agreed that all genes causing neuropathy as a key feature of a phenotype, even if in the context of other syndromic symptoms, should be included on this panel to minimise the risk of missing cases. For this reason it would now be appropriate to rate this gene as Green on R78.
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Gene: opa1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.96 OPA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' only to 'both mono- and biallelic'. Biallelic variants cause Behr syndrome (MIM# 210000) which is also associated with axonal sensorimotor peripheral neuropathy (PMID: 20157015; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Hereditary neuropathy or pain disorder v1.96 OPA1 Arina Puzriakova Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.95 OPA1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: OPA1.
Hereditary neuropathy v1.449 OPA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' only to 'both mono- and biallelic'. Biallelic variants cause Behr syndrome (MIM# 210000) which is also associated with axonal sensorimotor peripheral neuropathy (PMID: 20157015; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Hereditary neuropathy v1.449 OPA1 Arina Puzriakova Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.95 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic neuropathy, PEO, deafness, myelopathy, sensory-motor axonal neuropathy; Optic atrophy plus syndrome, 125250 to Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Hereditary neuropathy v1.448 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic atrophy plus syndrome, 125250; Optic neuropathy, PEO, deafness, myelopathy, sensory-motor axonal neuropathy to Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Unexplained kidney failure in young people v1.113 CFHR5 Eleanor Williams Phenotypes for gene: CFHR5 were changed from Haematuria; C3 glomerulopathy; kidney failure; macroscopic haematuria to C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency, OMIM:614809; Immune-complex-mediated MPGN; CFHR5 nephropathy; Haematuria; Chronic Kidney Disease; Proteinuria; End stage renal disease
Unexplained kidney failure in young people v1.112 CFHR5 Eleanor Williams Publications for gene: CFHR5 were set to PubMed: 20800271; 24067434
Unexplained kidney failure in young people v1.111 CFHR5 Eleanor Williams Classified gene: CFHR5 as Green List (high evidence)
Unexplained kidney failure in young people v1.111 CFHR5 Eleanor Williams Added comment: Comment on list classification: Promoting to green in light of external review and the fact that it is already green on the 'Unexplained paediatric onset end-stage renal disease' panel.
Unexplained kidney failure in young people v1.111 CFHR5 Eleanor Williams Gene: cfhr5 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.110 CFHR5 Eleanor Williams Mode of pathogenicity for gene: CFHR5 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
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Tag Q2_22_NHS_review tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Added comment: Comment on mode of inheritance: Daniel Gale confirms that the mode of inheritance should be monoallelic only.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Mode of inheritance for gene: CFHR5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.25 CFHR5 Eleanor Williams Phenotypes for gene: CFHR5 were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency,614809; Immune-complex-mediated MPGN; CFHR5 nephropathy to C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency, OMIM:614809; Immune-complex-mediated MPGN; CFHR5 nephropathy; Haematuria; Chronic Kidney Disease; Proteinuria; End stage renal disease
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.24 CFHR5 Eleanor Williams Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961; 22503529
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.23 CFHR5 Eleanor Williams Added comment: Comment on mode of pathogenicity: Updating as per reviewer suggestion
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.23 CFHR5 Eleanor Williams Mode of pathogenicity for gene: CFHR5 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mitochondrial disorders v2.99 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Likely inborn error of metabolism v2.245 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Possible mitochondrial disorder - nuclear genes v1.74 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic atrophy plus syndrome, 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Undiagnosed metabolic disorders v1.527 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Optic atrophy 1, 165500; {Glaucoma, normal tension, susceptibility to}, 606657; Optic atrophy plus syndrome, 125250; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Mitochondrial DNA maintenance disorder v1.8 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic atrophy plus syndrome, 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Monogenic hearing loss v2.242 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from #125250:Optic atrophy plus syndrome; #165500:Optic atrophy 1; #606657:{Glaucoma, normal tension, susceptibility to} to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250
Auditory Neuropathy Spectrum Disorde v1.9 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250
Ataxia and cerebellar anomalies - narrow panel v2.293 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Retinal disorders v2.256 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Eye Disorders to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250
Structural eye disease v1.122 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Glaucoma, normal tension, susceptibility to, 210000; Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to} 606657; Behr syndrome to {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Glaucoma (developmental) v1.42 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from {Glaucoma, normal tension, susceptibility to} 606657 to {Glaucoma, normal tension, susceptibility to}, OMIM:606657
Retinal disorders v2.255 MYO7A Arina Puzriakova Phenotypes for gene: MYO7A were changed from Eye Disorders to Usher syndrome, type 1B, OMIM:276900
Structural eye disease v1.121 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome, type 1, 267750 to Knobloch syndrome, type 1, OMIM:267750
Monogenic hearing loss v2.241 MYO7A Arina Puzriakova Phenotypes for gene: MYO7A were changed from hearing loss; Usher syndrome, type 1B, 276900; Nonsyndromic Hearing Loss, Dominant; #600060:Deafness, autosomal recessive 2; Nonsyndromic Hearing Loss, Recessive; #601317:Deafness, autosomal dominant 11 to Deafness, autosomal dominant 11, OMIM:601317; Deafness, autosomal recessive 2, OMIM:600060; Usher syndrome, type 1B, OMIM:276900
Retinal disorders v2.254 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch Syndrome Type I, 267750 to Knobloch syndrome, type 1, OMIM:267750
Structural eye disease v1.120 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 17546652; 22399687
Retinal disorders v2.253 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to
DDG2P v2.71 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from KNOBLOCH SYNDROME TYPE I 267750 to Knobloch syndrome, type 1, OMIM:267750
Fetal anomalies v1.854 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from KNOBLOCH SYNDROME TYPE I to Knobloch syndrome, type 1, OMIM:267750
Bilateral congenital or childhood onset cataracts v2.106 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome; high myopia; cataracts; vitreoretinal degeneration; retinal detachment to Knobloch syndrome, type 1, OMIM:267750
Early onset or syndromic epilepsy v2.511 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome, type 1 267750 to Knobloch syndrome, type 1, OMIM:267750
Early onset or syndromic epilepsy v2.510 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 19160445; 28602933; 28950998
Fetal anomalies v1.853 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to
DDG2P v2.70 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 10942434
Bilateral congenital or childhood onset cataracts v2.105 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to Aldahmesh et al (2011) J Genet Med 48(9):597-601; Williams et al (2008) Ophthal Genet 29:85-86; Suzuki et al (2002) Am J Hum Genet 71:1320-1329
Hydrocephalus v2.129 CLIC2 Sarah Leigh Classified gene: CLIC2 as Red List (low evidence)
Hydrocephalus v2.129 CLIC2 Sarah Leigh Gene: clic2 has been classified as Red List (Low Evidence).
Intellectual disability v3.1546 CLIC2 Sarah Leigh reviewed gene: CLIC2: Rating: RED; Mode of pathogenicity: None; Publications: 28333917, 31349857, 22814392; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.128 CLIC2 Sarah Leigh Publications for gene: CLIC2 were set to 22814392
Hydrocephalus v2.127 CLIC2 Sarah Leigh reviewed gene: CLIC2: Rating: RED; Mode of pathogenicity: None; Publications: 28333917, 31349857, 22814392; Phenotypes: ; Mode of inheritance: None
Cytopenia - NOT Fanconi anaemia v1.63 MPL Arina Puzriakova Added comment: Comment on mode of inheritance: The MOI on this panel should be reviewed at the next GMS panel update to determine the pertinent inheritance pattern (currently set to both AD/AR).

Biallelic variants cause thrombocytopenia (MIM# 604498) which in severe forms can present with pancytopenia, a phenotype that is within the scope of this panel. On the other hand, monoallelic variants are associated with thrombocythemia (MIM# 601977) which does not include features that may be relevant here. Therefore it may be appropriate to update the MOI to 'biallelic' only.
Cytopenia - NOT Fanconi anaemia v1.63 MPL Arina Puzriakova Mode of inheritance for gene: MPL was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.62 MPL Arina Puzriakova Tag Q2_22_MOI tag was added to gene: MPL.
Tag Q2_22_expert_review tag was added to gene: MPL.
Thrombocythaemia v1.3 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from Thrombocythemia 2, 601977 to Thrombocythemia 2, OMIM:601977
Cytopenia - NOT Fanconi anaemia v1.62 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from 601977 Thrombocythemia 2; 604498 Thrombocytopenia, congenital amegakaryocytic; Thrombocytopenia, congenital amegakaryocytic, 604498 to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Bleeding and platelet disorders v1.38 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from 604498 Thrombocytopenia, congenital amegakaryocytic to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Cytopenias and congenital anaemias v1.106 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from Inherited Bone Marrow Failure Syndromes - Thrombocytopenia; Congenital amegkaryocytic thrombocytopenia; Congenital Amegakaryocytic Thrombocytopenia; Amegakaryocytic Thrombocytopenia, Congenital; Thrombocytopenia, congenital amegakaryocytic, 604498 to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Inherited bleeding disorders v1.167 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from Congenital amegakaryocytic thrombocytopenia (CAMT) to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Structural eye disease v1.119 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, type 2A2, 609260; Eye Disorders to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Structural eye disease v1.118 MFN2 Arina Puzriakova Mode of inheritance for gene: MFN2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.63 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Optic Atrophy; Hereditary motor and sensory neuropathy VIA; Charcot-Marie-Tooth disease, axonal, type 2A2A (AD), 609260; Charcot-Marie-Tooth disease, axonal, type 2A2B (AR), 617087; Hereditary motor and sensory neuropathy VIA (AD), 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Hereditary neuropathy or pain disorder v1.94 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot Marie Tooth disease, type 2A2, 609260; Charcot-Marie-Tooth, Type 2 (Dominant); Hereditary motor and sensory neuropathy VI, 601152; MFN2 axonal neuropathy; Hereditary Motor and Sensory Neuropathy (Recessive) to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Mitochondrial disorders v2.98 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Charcot-Marie-Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Hereditary neuropathy v1.447 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth, Type 2 (Dominant); MFN2 axonal neuropathy; MFN2 axonal neuropathy; Charcot-Marie-Tooth, Type 2 (Dominant); Charcot Marie Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152; Hereditary motor and sensory neuropathy VI, 601152; Hereditary Motor and Sensory Neuropathy (Recessive); Hereditary Motor and Sensory Neuropathy (Recessive) to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Likely inborn error of metabolism v2.244 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, type 2A2, 609260; Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Possible mitochondrial disorder - nuclear genes v1.73 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Mitochondrial DNA depletion syndrome; Optic atrophy plus to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Undiagnosed metabolic disorders v1.526 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Charcot-Marie-Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Mitochondrial DNA maintenance disorder v1.7 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Mitochondrial DNA depletion syndrome; Optic atrophy plus to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Hereditary ataxia with onset in adulthood v2.155 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Dominant optic atrophy plus to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260
Inherited ovarian cancer (without breast cancer) v2.26 BRIP1 Sarah Leigh Added comment: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910)
{Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419
Inherited ovarian cancer (without breast cancer) v2.26 BRIP1 Sarah Leigh Phenotypes for gene: BRIP1 were changed from {Breast cancer, early-onset, susceptibility to}, OMIM:114480; Hereditary breast carcinoma, MONDO:0016419 to ovarian epithelial tumor, MONDO:0002229
Renal tubulopathies v2.50 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from Bartter syndrome, type 4b, digenic 613090 to Bartter syndrome, type 4b, digenic, OMIM:613090
Renal tubulopathies v2.49 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to 18310267
Renal tubulopathies v2.48 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936; 18310267; 32506365; 32488762; 30999883
Renal tubulopathies v2.47 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 8640224; 32506365
Renal tubulopathies v2.46 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 8640224
Renal tubulopathies v2.45 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936; 18310267
Intellectual disability v3.1546 AFF3 Arina Puzriakova commented on gene: AFF3
Intellectual disability v3.1546 AFF3 Arina Puzriakova Tag watchlist was removed from gene: AFF3.
Skeletal dysplasia v2.194 AFF3 Arina Puzriakova Classified gene: AFF3 as Amber List (moderate evidence)
Skeletal dysplasia v2.194 AFF3 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Skeletal dysplasia v2.194 AFF3 Arina Puzriakova Gene: aff3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.193 AFF3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: AFF3.
Skeletal dysplasia v2.193 AFF3 Arina Puzriakova reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18616733, 31388108, 33961779; Phenotypes: KINSSHIP syndrome, OMIM:619297; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.193 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to
Intellectual disability v3.1546 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108
Early onset or syndromic epilepsy v2.509 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108
Skeletal dysplasia v2.192 AFF3 Arina Puzriakova Mode of inheritance for gene: AFF3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1545 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures to KINSSHIP syndrome, OMIM:619297
Early onset or syndromic epilepsy v2.508 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures; KINSSHIP syndrome to KINSSHIP syndrome, OMIM:619297
Skeletal dysplasia v2.191 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from No OMIM or G2P phenotype to KINSSHIP syndrome, OMIM:619297
Renal tubulopathies v2.44 CLCNKB Sarah Leigh Added comment: Comment on phenotypes: Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria
Renal tubulopathies v2.44 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090 to Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090
Renal tubulopathies v2.43 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936; 18310267
Early onset or syndromic epilepsy v2.507 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to 31271740; 34918187; 35346037
Phenotypes for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
----
Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
----
Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
------
In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Intellectual disability v3.1544 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Phenotypes for gene: DTYMK were set to 31271740; 34918187; 35346037
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
----
Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
----
Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
------
In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Renal tubulopathies v2.42 CLCNKB Sarah Leigh Added comment: Comment on phenotypes: Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria
Renal tubulopathies v2.42 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria; Bartter syndrome, type 3, 607394 to Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090
Renal tubulopathies v2.41 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936
Atypical haemolytic uraemic syndrome v2.15 CFI Sarah Leigh Deleted their comment
Atypical haemolytic uraemic syndrome v2.15 CFI Sarah Leigh commented on gene: CFI: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in this panel.
Unexplained young onset end-stage renal disease v1.36 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923; Complement factor I deficiency, OMIM:610984
Unexplained young onset end-stage renal disease v1.35 CFI Sarah Leigh Publications for gene: CFI were set to 16621965; 15173250
Unexplained young onset end-stage renal disease v1.34 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Unexplained young onset end-stage renal disease v1.34 CFI Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.109 CFI Sarah Leigh Mode of inheritance for gene: CFI was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.108 CFI Sarah Leigh Tag Q2_22_MOI was removed from gene: CFI.
Atypical haemolytic uraemic syndrome v2.15 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Atypical haemolytic uraemic syndrome v2.14 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Atypical haemolytic uraemic syndrome v2.13 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Atypical haemolytic uraemic syndrome v2.12 CFI Sarah Leigh Publications for gene: CFI were set to 16621965; 17597211; 15173250; 23685748
Atypical haemolytic uraemic syndrome v2.11 CFI Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in this panel.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Atypical haemolytic uraemic syndrome v2.11 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Unexplained kidney failure in young people v1.108 CFI Sarah Leigh changed review comment from: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Unexplained kidney failure in young people v1.108 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Unexplained kidney failure in young people v1.107 CFI Sarah Leigh Publications for gene: CFI were set to 15173250; 16621965;
Unexplained kidney failure in young people v1.106 CFI Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.106 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Atypical haemolytic uraemic syndrome v2.11 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923
COVID-19 research v1.123 CFI Sarah Leigh Mode of inheritance for gene: CFI was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood solid tumours v2.32 CDKN1C Sarah Leigh Publications for gene: CDKN1C were set to 10424812
Childhood solid tumours v2.31 CDKN1C Sarah Leigh Tag Q2_22_MOI tag was added to gene: CDKN1C.
Childhood solid tumours v2.31 CDKN1C Sarah Leigh reviewed gene: CDKN1C: Rating: ; Mode of pathogenicity: None; Publications: 7550351, 7729684, 8610162).; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Familial rhabdomyosarcoma v1.5 CDKN1C Sarah Leigh Mode of inheritance for gene: CDKN1C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Childhood solid tumours cancer susceptibility v1.20 CDKN1C Sarah Leigh Mode of inheritance for gene: CDKN1C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.22 CFHR5 Daniel Gale reviewed gene: CFHR5: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 20800271, 21566112, 30844074, 28729035, 32928961, 24067434, 27490940, 33753502, 30197990, 24067434; Phenotypes: Haematuria, C3 glomerulopathy, Chronic Kidney Disease, Proteinuria, End stage renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Unexplained kidney failure in young people v1.106 CFHR5 Daniel Gale reviewed gene: CFHR5: 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: 20800271, 21566112, 30844074, 28729035, 32928961, 24067434, 27490940, 33753502, 30197990, 24067434; Phenotypes: Haematuria, C3 glomerulopathy, Chronic Kidney Disease, Proteinuria, End stage renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.243 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Likely inborn error of metabolism v2.243 C19orf12 Sarah Leigh edited their review of gene: C19orf12: Added comment: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 29295770, 31087512; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.525 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Undiagnosed metabolic disorders v1.525 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.108 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Parkinson Disease and Complex Parkinsonism v1.108 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.62 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Optic neuropathy v2.62 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.272 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Adult onset neurodegenerative disorder v2.272 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset dystonia v1.117 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset dystonia v1.117 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.292 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary spastic paraplegia v1.292 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.133 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Childhood onset hereditary spastic paraplegia v2.133 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset hereditary spastic paraplegia v1.97 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset hereditary spastic paraplegia v1.97 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Likely inborn error of metabolism v2.243 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Neurodegeneration with brain iron accumulation 4, 614298; Mitochondrial Membrane Protein-Associated Neurodegeneration to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Childhood onset dystonia, chorea or related movement disorder v1.227 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from neurodegeneration with brain iron accumulation-4, 614298; mitochondrial membrane protein-associated neurodegeneration; Dystonia to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Undiagnosed metabolic disorders v1.524 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Neurodegeneration with brain iron accumulation 4, 614298; Mitochondrial Membrane Protein-Associated Neurodegeneration to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Adult onset neurodegenerative disorder v2.272 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation 4, OMIM: 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Adult onset neurodegenerative disorder v2.271 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Dystonia; neurodegeneration with brain iron accumulation-4, OMIM:614298 to Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Adult onset hereditary spastic paraplegia v1.97 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Childhood onset hereditary spastic paraplegia v2.133 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Optic neuropathy v2.62 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from SPASTIC PARAPLEGIA 43, AUTOSOMAL RECESSIVE, 615043; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Hereditary spastic paraplegia v1.291 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Structural basal ganglia disorders v1.32 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Early onset dystonia v1.116 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Dystonia; mitochondrial membrane protein-associated neurodegeneration; neurodegeneration with brain iron accumulation-4 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Parkinson Disease and Complex Parkinsonism v1.107 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Dystonia; mitochondrial membrane protein-associated neurodegeneration; Neurodegeneration with brain iron accumulation 4 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Early onset dystonia v1.115 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.106 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Early onset dystonia v1.114 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Structural basal ganglia disorders v1.31 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Hereditary spastic paraplegia v1.290 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to Landoure (2013)
Optic neuropathy v2.61 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27772766; 26187298; 24209434; 22584950
Childhood onset hereditary spastic paraplegia v2.132 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23857908; 26539891
Adult onset hereditary spastic paraplegia v1.96 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23857908; 26539891
Adult onset neurodegenerative disorder v2.270 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23278385; Landoure (2013)
Likely inborn error of metabolism v2.242 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27604308
Undiagnosed metabolic disorders v1.523 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27604308
Adult onset dystonia, chorea or related movement disorder v1.169 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Childhood onset dystonia, chorea or related movement disorder v1.226 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Intellectual disability v3.1544 KDM5B Arina Puzriakova Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 to Intellectual developmental disorder, autosomal recessive 65, OMIM:618109
Monogenic hearing loss v2.240 KCNQ4 Arina Puzriakova Phenotypes for gene: KCNQ4 were changed from #600101:Deafness, autosomal dominant 2A to Deafness, autosomal dominant 2A, OMIM:600101
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.69 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Resistance to insulin-like growth factor I to Insulin-like growth factor I, resistance to, OMIM:270450
Fetal anomalies v1.852 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO to Insulin-like growth factor I, resistance to, OMIM:270450
Severe microcephaly v2.300 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin-like growth factor I, resistance to 270450 to Insulin-like growth factor I, resistance to, OMIM:270450
IUGR and IGF abnormalities v1.52 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin‐likegrowthfactorI,resistanceto,270450; Insulin-Like Growth Factor I Resistance to Insulin-like growth factor I, resistance to, OMIM:270450
Intellectual disability v3.1543 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Gene2Phenotype confirmed gene with ID HPO; Insulin-like growth factor I, resistance to, 270450; developmental delay to Insulin-like growth factor I, resistance to, OMIM:270450
Silver Russell syndrome v1.12 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin-like growth factor I, resistance to 270450 to Insulin-like growth factor I, resistance to, OMIM:270450
Early onset or syndromic epilepsy v2.507 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925
Intellectual disability v3.1542 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Inherited white matter disorders v1.158 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy; Megalencephalic leukoencephalopathy with subcortical cysts (MLC); Megalencephalic leukoencephalopathy with subcortical cysts 2A; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Adult onset leukodystrophy v1.41 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, 613926 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
White matter disorders and cerebral calcification - narrow panel v1.236 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts (MLC); General Leukodystrophy & Mitochondrial Leukoencephalopathy; Megalencephalic leukoencephalopathy with subcortical cysts 2A; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Cytopenias and congenital anaemias v1.105 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903 to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Hereditary persistence of fetal hemoglobin, OMIM:141749; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Rare anaemia v1.40 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903 to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Hereditary persistence of fetal hemoglobin, OMIM:141749; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Cytopenias and congenital anaemias v1.104 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from Globin Disorder; Delta-beta thalassemia (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 141749; Erythremias, beta-; Heinz body anemias, beta- (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 140700; Hereditary persistence of fetal hemoglobin,(MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown),141749; Methemoglobinemias, beta-; Sickle cell anemia (BIALLELIC, autosomal or pseudoautosomal),603903; Thalassemia-beta, dominant inclusion-body, 603902; Thalassemias, beta-,(BIALLELIC, autosomal or pseudoautosomal), 613985 to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Rare anaemia v1.39 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from 603902 Dominand inclusion body beta thalassaemia; Erythremias, beta-; Heinz body anemias, beta- (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 140700; Globin Disorder; 141749 Delta-beta thalassaemia; 613985 Beta thalassaemia; Methemoglobinemias, beta-; Thalassemias, beta-,(BIALLELIC, autosomal or pseudoautosomal), 613985; 603903 Sickle cell disease; 603902 Thalassemia-beta, dominant inclusion-body; Sickle cell anemia (BIALLELIC, autosomal or pseudoautosomal),603903; Hereditary persistence of fetal hemoglobin,(MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown),141749; Thalassemia-beta, dominant inclusion-body, 603902; Delta-beta thalassemia (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 141749; 613985 Thalassemia, beta to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Corneal dystrophy v1.12 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type 105120 to Amyloidosis, Finnish type, OMIM:105120
Periodic fever syndromes v1.30 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis; Amyloidosis, Finnish type, 105120 to Amyloidosis, Finnish type, OMIM:105120
Hereditary systemic amyloidosis v1.13 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type 105120 to Amyloidosis, Finnish type, OMIM:105120
Corneal dystrophy v1.11 GRHL2 Arina Puzriakova Phenotypes for gene: GRHL2 were changed from Corneal dystrophy, posterior polymorphous, 4 618031 to Corneal dystrophy, posterior polymorphous, 4, OMIM:618031
Monogenic hearing loss v2.239 GRHL2 Arina Puzriakova Phenotypes for gene: GRHL2 were changed from hearing loss; Deafness, autosomal dominant 28, 608641; #616029: Ectodermal dysplasia/short stature syndrome to Deafness, autosomal dominant 28, OMIM:608641; Ectodermal dysplasia/short stature syndrome, OMIM:616029
Ectodermal dysplasia v1.39 GRHL2 Arina Puzriakova Phenotypes for gene: GRHL2 were changed from to Ectodermal dysplasia/short stature syndrome, OMIM:616029
Ectodermal dysplasia v1.38 GRHL2 Arina Puzriakova Publications for gene: GRHL2 were set to 25152456
Ectodermal dysplasia v1.37 GRHL2 Arina Puzriakova Tag Q2_22_rating tag was added to gene: GRHL2.
Tag Q2_22_expert_review tag was added to gene: GRHL2.
Ectodermal dysplasia v1.37 GRHL2 Arina Puzriakova reviewed gene: GRHL2: Rating: ; Mode of pathogenicity: None; Publications: 27612988; Phenotypes: Ectodermal dysplasia/short stature syndrome, OMIM:616029; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.292 PEX6 Sarah Leigh Tag Q2_22_MOI was removed from gene: PEX6.
Tag Q2_22_rating tag was added to gene: PEX6.
Ataxia and cerebellar anomalies - narrow panel v2.292 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Ataxia and cerebellar anomalies - narrow panel v2.292 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.291 PEX6 Sarah Leigh Classified gene: PEX6 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.291 PEX6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for PEX6 to be green on this panel.
Ataxia and cerebellar anomalies - narrow panel v2.291 PEX6 Sarah Leigh Gene: pex6 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.290 PEX6 Sarah Leigh gene: PEX6 was added
gene: PEX6 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_22_MOI tags were added to gene: PEX6.
Mode of inheritance for gene: PEX6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PEX6 were set to 25655951; 29220678
Phenotypes for gene: PEX6 were set to Peroxisome biogenesis disorder 4B, OMIM:614863
Penetrance for gene: PEX6 were set to Incomplete
Mode of pathogenicity for gene: PEX6 was set to Other
Review for gene: PEX6 was set to GREEN
Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).
Sources: Literature
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova edited their review of gene: NCAPD3: Changed rating: GREEN
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Classified gene: NCAPD3 as Amber List (moderate evidence)
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Added comment: Comment on list classification: Given the discovery of a third patient in the NHS presenting a phenotype consistent with previous reports and functional studies providing a plausible disease mechanism, this gene should now be promoted to Green at the next GMS panel update to ensure detection of cases.
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Gene: ncapd3 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova Tag Q2_21_MOI was removed from gene: SLURP1.
Tag Q2_22_MOI tag was added to gene: SLURP1.
Severe microcephaly v2.298 NCAPD3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: NCAPD3.
Tag Q2_22_NHS_review tag was added to gene: NCAPD3.
Severe microcephaly v2.298 NCAPD3 Arina Puzriakova Phenotypes for gene: NCAPD3 were changed from Microcephaly 22, primary, autosomal recessive, 617984 to Microcephaly 22, primary, autosomal recessive, OMIM:617984
Severe microcephaly v2.297 NAPB Arina Puzriakova Entity copied from Genetic epilepsy syndromes v2.506
Severe microcephaly v2.297 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Severe microcephaly. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Intellectual disability v3.1541 NAPB Arina Puzriakova Entity copied from Genetic epilepsy syndromes v2.506
Intellectual disability v3.1541 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Intellectual disability. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Classified gene: NAPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 3 unrelated families (4 affected individuals) with distinct homozygous variants in this gene, universally presenting seizures, profound ID and microcephaly. Pathogenicity is supported by a complimentary knockout mouse model demonstrating recurrent post-natal epileptic seizures which were lethal in some mice.
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Gene: napb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.505 NAPB Arina Puzriakova Tag Q2_22_rating tag was added to gene: NAPB.
Tag Q2_22_NHS_review tag was added to gene: NAPB.
Pulmonary fibrosis familial v0.8 RPA1 Arina Puzriakova changed review comment from: Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerge.; to: Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerges.
Pulmonary fibrosis familial v0.8 RPA1 Arina Puzriakova edited their review of gene: RPA1: Changed rating: AMBER
Pulmonary fibrosis familial v0.8 RPA1 Arina Puzriakova Classified gene: RPA1 as Amber List (moderate evidence)
Pulmonary fibrosis familial v0.8 RPA1 Arina Puzriakova Added comment: Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerge.
Pulmonary fibrosis familial v0.8 RPA1 Arina Puzriakova Gene: rpa1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.61 RPA1 Arina Puzriakova Classified gene: RPA1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.61 RPA1 Arina Puzriakova Added comment: Comment on list classification: Despite the heterogenous phenotypes observed, there are sufficient cases (3) with hematopoietic manifestations to warrant a green rating on this panel at the next GMS review.
Cytopenia - NOT Fanconi anaemia v1.61 RPA1 Arina Puzriakova Gene: rpa1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.60 RPA1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: RPA1.
Pulmonary fibrosis familial v0.7 RPA1 Arina Puzriakova Entity copied from Cytopenia - NOT Fanconi anaemia v1.60
Pulmonary fibrosis familial v0.7 RPA1 Arina Puzriakova gene: RPA1 was added
gene: RPA1 was added to Pulmonary fibrosis familial. Sources: Literature
Mode of inheritance for gene: RPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPA1 were set to 34767620
Phenotypes for gene: RPA1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767
Penetrance for gene: RPA1 were set to Incomplete
Mode of pathogenicity for gene: RPA1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Cytopenia - NOT Fanconi anaemia v1.60 RPA1 Arina Puzriakova Penetrance for gene RPA1 was set from to unknown
Cytopenia - NOT Fanconi anaemia v1.59 RPA1 Arina Puzriakova Publications for gene: RPA1 were set to
Cytopenia - NOT Fanconi anaemia v1.58 RPA1 Arina Puzriakova reviewed gene: RPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34767620; Phenotypes: Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.58 RPA1 Arina Puzriakova Phenotypes for gene: RPA1 were changed from bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations. to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767
Intellectual disability v3.1540 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Hereditary neuropathy or pain disorder v1.93 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from motor neuropathy to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Early onset or syndromic epilepsy v2.505 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from SLC5A6-related Neurodevelopmental Disorder to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Likely inborn error of metabolism v2.241 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from SLC5A6-related Neurodevelopmental Disorder to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Intellectual disability v3.1539 RAC3 Arina Puzriakova Phenotypes for gene: RAC3 were changed from Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Fetal anomalies v1.851 RAC3 Arina Puzriakova Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Fetal anomalies v1.850 RAC3 Arina Puzriakova Classified gene: RAC3 as Amber List (moderate evidence)
Fetal anomalies v1.850 RAC3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.850 RAC3 Arina Puzriakova Gene: rac3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.849 RAC3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: RAC3.
Retinal disorders v2.252 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to 28575650; 28514307
White matter disorders and cerebral calcification - narrow panel v1.235 NDUFV2 Arina Puzriakova Classified gene: NDUFV2 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.235 NDUFV2 Arina Puzriakova Gene: ndufv2 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.234 NDUFV2 Arina Puzriakova gene: NDUFV2 was added
gene: NDUFV2 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
watchlist tags were added to gene: NDUFV2.
Mode of inheritance for gene: NDUFV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV2 were set to 33811136
Phenotypes for gene: NDUFV2 were set to Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229; Progressive cavitating leukoencephalopathy, MONDO:0015349
Review for gene: NDUFV2 was set to AMBER
Added comment: Liu et al., 2022 (PMID: 33811136) report on two sibling pairs of two unrelated Chinese families presenting with progressive cavitating leukoencephalopathy associated with distinct biallelic variants in this gene. Functional analyses demonstrated impaired structural stability and function of the NDUFV2 protein and complex I deficiency was confirmed in affected individuals' fibroblasts and a muscle biopsy.

This is the first report linking NDUFV2 with a leukoencephalopathy phenotype and therefore rating as Amber for now until further cases emerge.
Sources: Literature