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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 NOT PMP22 copy number 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 NOT PMP22 copy number 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 NOT PMP22 copy number v1.103 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.103 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.102 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to PMID: 35013551
Severe Paediatric Disorders v1.123 PRODH Sarah Leigh Classified gene: PRODH as Green List (high evidence)
Severe Paediatric Disorders v1.123 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).
Severe Paediatric Disorders v1.123 PRODH Sarah Leigh Gene: prodh has been classified as Green List (High Evidence).
Genetic epilepsy syndromes 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).
Severe Paediatric Disorders v1.122 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
Genetic epilepsy syndromes 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
Inborn errors 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
Inborn errors of metabolism v2.254 PRODH Sarah Leigh Classified gene: PRODH as Green List (high evidence)
Inborn errors 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).
Inborn errors 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.

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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.
Genetic epilepsy syndromes v2.523 RALGAPB Arina Puzriakova Classified gene: RALGAPB as Red List (low evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.522 CELF2 Arina Puzriakova Classified gene: CELF2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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 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.
Inborn errors of metabolism v2.253 TARS2 Arina Puzriakova Mode of inheritance for gene: TARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
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
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 or chorea or related movement disorder v1.232 TAZ Arina Puzriakova commented on gene: TAZ
Hereditary neuropathy NOT PMP22 copy number v1.101 TAZ Arina Puzriakova commented on gene: TAZ
Cardiomyopathies - including childhood onset 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
Inborn errors 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 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 or chorea or related movement disorder v1.232 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Hereditary neuropathy NOT PMP22 copy number v1.101 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Cardiomyopathies - including childhood onset 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.
Inborn errors 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 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 NOT PMP22 copy number 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 NOT PMP22 copy number 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
Craniosynostosis 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.
Craniosynostosis 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 or 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 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.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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.
Diabetes - neonatal onset 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 v2.548 OAS1 Arina Puzriakova Tag gene-checked tag was added to gene: OAS1.
Cardiomyopathies - including childhood onset v1.70 NRAP Arina Puzriakova Tag gene-checked tag was added to gene: NRAP.
Dilated cardiomyopathy - adult and teen 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.
Genetic epilepsy syndromes 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.
Cardiomyopathies - including childhood onset v1.70 MYLK3 Arina Puzriakova Tag gene-checked tag was added to gene: MYLK3.
Dilated cardiomyopathy - adult and teen 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 v2.548 ZNF341 Arina Puzriakova Tag gene-checked tag was added to gene: ZNF341.
Genetic epilepsy syndromes 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
Severe Paediatric Disorders v1.121 PAPPA2 Arina Puzriakova Mode of inheritance for gene: PAPPA2 was changed from MITOCHONDRIAL to BIALLELIC, autosomal or pseudoautosomal
ClinGen_Familial thoracic aortic aneurysm and aortic dissection v0.11 COL4A5 Arina Puzriakova Mode of inheritance for gene: COL4A5 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)
Mitochondrial disorders v2.103 MT-TR Eleanor Williams Tag gene-checked tag was added to gene: MT-TR.
Inborn errors 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.
Leber hereditary optic neuropathy v1.11 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
Genetic epilepsy syndromes 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
Cardiomyopathies - including childhood onset 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.
Leber hereditary optic neuropathy v1.11 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.
Hearing loss v2.242 MT-TS1 Eleanor Williams Tag gene-checked tag was added to gene: MT-TS1.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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 v2.548 SASH3 Eleanor Williams Tag gene-checked tag was added to gene: SASH3.
Genetic epilepsy syndromes 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.
Cardiomyopathies - including childhood onset 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 paediatric 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.
Inborn errors 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 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.
Genetic epilepsy syndromes v2.519 SNX27 Eleanor Williams Tag gene-checked tag was added to gene: SNX27.
Primary immunodeficiency 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.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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 paediatric 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.
Genetic epilepsy syndromes 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 paediatric 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 or 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.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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 paediatric 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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 or 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.
Hereditary spastic paraplegia - childhood onset v2.137 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
Primary immunodeficiency 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.
Growth failure in early childhood v1.105 NHLRC2 Eleanor Williams Tag gene-checked tag was added to gene: NHLRC2.
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.
Inborn errors 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.
Inborn errors 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 NOT PMP22 copy number v1.101 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
Hereditary ataxia - adult onset 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.
Inborn errors 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
Wilms tumour with features suggestive of predisposition v0.5 TRIM28 Eleanor Williams Tag gene-checked tag was added to gene: TRIM28.
Tumour predisposition - childhood onset v2.33 TRIM28 Eleanor Williams Tag gene-checked tag was added to gene: TRIM28.
Hypertrophic cardiomyopathy - teen and adult 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.
Inborn errors 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
Inborn errors 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
Inborn errors 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.
Genetic epilepsy syndromes 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 paediatric 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.
Inborn errors 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.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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.
Cataracts v2.108 ZNF526 Eleanor Williams Tag gene-checked tag was added to gene: ZNF526.
Adult onset movement disorder v1.170 KIAA1161 Eleanor Williams Tag gene-checked tag was added to gene: KIAA1161.
Neurodegenerative disorders - adult onset 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.
Genetic epilepsy syndromes 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.
Hereditary spastic paraplegia - childhood onset 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.
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.
Inborn errors 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.
Leber hereditary optic neuropathy v1.11 DNAJC30 Eleanor Williams Tag gene-checked tag was added to gene: DNAJC30.
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.
Genetic epilepsy syndromes 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 NOT PMP22 copy number v1.101 C1orf194 Eleanor Williams Tag new-gene-name tag was added to gene: C1orf194.
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.101 C1orf194 Eleanor Williams Tag gene-checked tag was added to gene: C1orf194.
Genetic epilepsy syndromes 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
Inborn errors of metabolism v2.250 TRAP1 Catherine Snow Tag gene-checked tag was added to gene: TRAP1.
Inborn errors of metabolism v2.250 MT-ND5 Catherine Snow Tag gene-checked tag was added to gene: MT-ND5.
Inborn errors of metabolism v2.250 MT-ND4L Catherine Snow Tag gene-checked tag was added to gene: MT-ND4L.
Inborn errors of metabolism v2.250 MT-ND4 Catherine Snow Tag gene-checked tag was added to gene: MT-ND4.
Inborn errors of metabolism v2.250 MT-ND3 Catherine Snow Tag gene-checked tag was added to gene: MT-ND3.
Inborn errors of metabolism v2.250 MT-ND2 Catherine Snow Tag gene-checked tag was added to gene: MT-ND2.
Inborn errors of metabolism v2.250 MT-ND1 Catherine Snow Tag gene-checked tag was added to gene: MT-ND1.
Genetic epilepsy syndromes v2.518 TUBGCP2 Catherine Snow Tag gene-checked tag was added to gene: TUBGCP2.
Primary immunodeficiency v2.548 ZNFX1 Catherine Snow Tag gene-checked tag was added to gene: ZNFX1.
Primary immunodeficiency v2.548 TRIM22 Catherine Snow Tag gene-checked tag was added to gene: TRIM22.
Primary immunodeficiency v2.548 TNFRSF9 Catherine Snow Tag gene-checked tag was added to gene: TNFRSF9.
Primary immunodeficiency v2.548 C17orf62 Catherine Snow Tag gene-checked tag was added to gene: C17orf62.
Primary immunodeficiency v2.548 ALPI Catherine Snow Tag gene-checked tag was added to gene: ALPI.
Primary immunodeficiency 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 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Genetic epilepsy syndromes 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 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.
Genetic epilepsy syndromes 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.
Tumour predisposition - childhood onset 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.
Inborn errors 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.
Inborn errors 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 paediatric 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Inborn errors 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.
Cataracts v2.108 CYP51A1 Sarah Leigh Publications for gene: CYP51A1 were set to 22935719; 25148791
Cataracts v2.107 CYP51A1 Sarah Leigh Tag gene-checked tag was added to gene: CYP51A1.
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 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.
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.
Inborn errors 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.
Inborn errors 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.
Leber hereditary optic neuropathy v1.11 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 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.
Genetic epilepsy syndromes 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 paediatric onset end-stage renal disease v1.36 ITSN1 Arina Puzriakova Tag gene-checked tag was added to gene: ITSN1.
Genetic epilepsy syndromes 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 paediatric onset end-stage renal disease v1.36 FAT1 Arina Puzriakova Tag gene-checked tag was added to gene: FAT1.
Wilms tumour with features suggestive of predisposition v0.5 CTR9 Sarah Leigh Tag gene-checked tag was added to gene: CTR9.
Tumour predisposition - childhood onset v2.33 CTR9 Sarah Leigh Tag gene-checked tag was added to gene: CTR9.
Genetic epilepsy syndromes 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 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 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 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 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 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 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.
Cardiomyopathies - including childhood onset v1.70 MYH6 Sarah Leigh Publications for gene: MYH6 were set to
Cardiomyopathies - including childhood onset 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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)
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Wilms tumour with features suggestive of predisposition v0.5 Eleanor Williams Panel status changed from internal to public
Genetic epilepsy syndromes 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
Growth failure in early childhood v1.105 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
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
Genetic epilepsy syndromes 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
Inborn errors 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
Inborn errors 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
Inborn errors 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 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 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 v2.545 FASLG Eleanor Williams Tag Q2_22_MOI tag was added to gene: FASLG.
Primary immunodeficiency 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 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
Inborn errors of metabolism v2.249 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: Hyperinsulinemic hypoglycemia, familial, 7;mainly ketosis with borderline reduction in glucose
Inborn errors 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 NOT PMP22 copy number 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 NOT PMP22 copy number 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 NOT PMP22 copy number 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
Inborn errors 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
Inborn errors 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 NOT PMP22 copy number 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 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 NOT PMP22 copy number 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 NOT PMP22 copy number v1.100 SETX Sarah Leigh Phenotypes for gene: SETX were changed from to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002
Primary immunodeficiency 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 dystrophies 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 NOT PMP22 copy number 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 NOT PMP22 copy number 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 or 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
Inborn errors 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 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 or 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 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 - adult onset 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 - adult onset 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 - adult onset 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).
Hereditary spastic paraplegia - adult onset 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
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.517 CACNA2D1 Sarah Leigh reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v2.517 CACNA2D1 Sarah Leigh Classified gene: CACNA2D1 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.516 CACNA2D1 Sarah Leigh Publications for gene: CACNA2D1 were set to 35293990
Genetic epilepsy syndromes v2.515 KCNC2 Sarah Leigh Classified gene: KCNC2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.515 KCNC2 Sarah Leigh Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.514 KCNC2 Sarah Leigh Tag Q2_22_rating tag was added to gene: KCNC2.
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.513 DTYMK Sarah Leigh Classified gene: DTYMK as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.513 DTYMK Sarah Leigh Gene: dtymk has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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 syndromes 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 syndromes 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
Craniosynostosis 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 or chorea or related movement disorder v1.230 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to
Childhood onset dystonia or 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 or chorea or related movement disorder v1.228 HSPD1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: HSPD1.
Childhood onset dystonia or 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 or 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)
Genetic epilepsy syndromes v2.512 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Craniosynostosis v2.74 NFIA Eleanor Williams Classified gene: NFIA as Amber List (moderate evidence)
Craniosynostosis v2.74 NFIA Eleanor Williams Gene: nfia has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders - adult onset 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
Craniosynostosis 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.
Inborn errors 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)
Craniosynostosis v2.73 NFIA Eleanor Williams Classified gene: NFIA as Red List (low evidence)
Craniosynostosis 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.
Craniosynostosis 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)
Craniosynostosis v2.72 NFIA Eleanor Williams Phenotypes for gene: NFIA were changed from to Metopic synostosis, hydrocephalus, thin corpus callosum, mild developmental delay, autism, macrocephaly
Craniosynostosis v2.71 NFIA Eleanor Williams Mode of inheritance for gene: NFIA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Craniosynostosis v2.70 NFIA Eleanor Williams Publications for gene: NFIA were set to
Hereditary spastic paraplegia - adult onset v1.101 HSPD1 Arina Puzriakova Classified gene: HSPD1 as Amber List (moderate evidence)
Hereditary spastic paraplegia - adult onset 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.
Hereditary spastic paraplegia - adult onset 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)
Hereditary spastic paraplegia - adult onset 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
Hereditary spastic paraplegia - adult onset 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.
Hereditary spastic paraplegia - adult onset 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
Hereditary spastic paraplegia - childhood onset v2.137 HSPD1 Arina Puzriakova Classified gene: HSPD1 as Amber List (moderate evidence)
Hereditary spastic paraplegia - childhood onset 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.
Hereditary spastic paraplegia - childhood onset v2.137 HSPD1 Arina Puzriakova Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia - childhood onset v2.136 HSPD1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: HSPD1.
Hereditary spastic paraplegia - childhood onset v2.136 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to 17420924; 10677329; 11898127
Hereditary spastic paraplegia - childhood onset 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.
Hereditary spastic paraplegia - childhood onset 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
Hereditary spastic paraplegia - childhood onset v2.134 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Hereditary spastic paraplegia - adult onset 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
Hereditary spastic paraplegia - adult onset 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 dystrophy 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
Tumour predisposition - childhood onset 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 - adult onset 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 NOT PMP22 copy number v1.98 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Hereditary neuropathy NOT PMP22 copy number v1.97 OPA1 Arina Puzriakova Classified gene: OPA1 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.97 OPA1 Arina Puzriakova Gene: opa1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number 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 NOT PMP22 copy number 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 NOT PMP22 copy number 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 v2.26 CFHR5 Eleanor Williams Tag Q2_22_NHS_review tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis 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 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 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 v2.24 CFHR5 Eleanor Williams Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961; 22503529
Membranoproliferative glomerulonephritis v2.23 CFHR5 Eleanor Williams Added comment: Comment on mode of pathogenicity: Updating as per reviewer suggestion
Membranoproliferative glomerulonephritis 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
Inborn errors 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
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 Disorder 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
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
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
Genetic epilepsy syndromes v2.511 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome, type 1 267750 to Knobloch syndrome, type 1, OMIM:267750
Genetic epilepsy syndromes 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
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 NOT PMP22 copy number 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
Inborn errors 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 - adult onset 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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 paediatric 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 paediatric onset end-stage renal disease v1.35 CFI Sarah Leigh Publications for gene: CFI were set to 16621965; 15173250
Unexplained paediatric onset end-stage renal disease v1.34 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Unexplained paediatric 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
Tumour predisposition - childhood onset v2.32 CDKN1C Sarah Leigh Publications for gene: CDKN1C were set to 10424812
Tumour predisposition - childhood onset v2.31 CDKN1C Sarah Leigh Tag Q2_22_MOI tag was added to gene: CDKN1C.
Tumour predisposition - childhood onset 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 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
Inborn errors of metabolism v2.243 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Inborn errors 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
Neurodegenerative disorders - adult onset v2.272 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Neurodegenerative disorders - adult onset 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
Hereditary spastic paraplegia - childhood onset v2.133 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Hereditary spastic paraplegia - childhood onset 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
Hereditary spastic paraplegia - adult onset 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
Hereditary spastic paraplegia - adult onset v1.97 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Inborn errors 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 or 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
Neurodegenerative disorders - adult onset 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
Neurodegenerative disorders - adult onset 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
Hereditary spastic paraplegia - adult onset 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
Hereditary spastic paraplegia - childhood onset 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
Hereditary spastic paraplegia - childhood onset v2.132 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23857908; 26539891
Hereditary spastic paraplegia - adult onset v1.96 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23857908; 26539891
Neurodegenerative disorders - adult onset v2.270 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23278385; Landoure (2013)
Inborn errors 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 movement disorder v1.169 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Childhood onset dystonia or chorea or related movement disorder v1.226 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Severe Paediatric Disorders v1.120 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 30847515
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
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
Growth failure in early childhood v1.104 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin-Like Growth Factor I Resistance; Insulin likegrowthfactorI,resistanceto,270450; 15q-Del to Insulin-like growth factor I, resistance to, OMIM:270450
Craniosynostosis 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
Genetic epilepsy syndromes 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
White matter disorders - adult onset 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 dystrophies 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
Amyloidosis v1.13 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type 105120 to Amyloidosis, Finnish type, OMIM:105120
Corneal dystrophies 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
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
Genetic epilepsy syndromes v2.506 NAPB Arina Puzriakova Classified gene: NAPB as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.506 NAPB Arina Puzriakova Gene: napb has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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 NOT PMP22 copy number v1.93 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from motor neuropathy to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Genetic epilepsy syndromes v2.505 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from SLC5A6-related Neurodevelopmental Disorder to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Inborn errors 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
Rare genetic inflammatory skin disorders v1.54 GJB4 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both monoallelic and biallelic' to just 'monoallelic' as the literature only reports heterozygous (monoallelic) variants associated with EKVP. Rare biallelic forms of EKVP have so far only been reported for GJB3 (OMIM:133200).
Rare genetic inflammatory skin disorders v1.54 GJB4 Arina Puzriakova Mode of inheritance for gene: GJB4 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v1.53 GJB4 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: GJB4.
Pigmentary skin disorders v1.50 GJB4 Arina Puzriakova Phenotypes for gene: GJB4 were changed from Erythrokeratodermia variabilis; EKVP2; ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2 to Erythrokeratodermia variabilis et progressiva 2, OMIM:617524
Palmoplantar keratoderma and erythrokeratodermas v1.24 GJB4 Arina Puzriakova Phenotypes for gene: GJB4 were changed from Erythrokeratodermia variabilis et progressiva 2, 617524 to Erythrokeratodermia variabilis et progressiva 2, OMIM:617524
Intellectual disability v3.1538 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.92 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 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
Hereditary neuropathy v1.446 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 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
Possible mitochondrial disorder - nuclear genes v1.72 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 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 Paediatric Disorders v1.119 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, 607706; Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth disease, recessive intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Hereditary neuropathy NOT PMP22 copy number v1.91 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease, recessive intermediate, A, 608340; Charcot-Marie-Tooth with Vocal Cord Paresis (recessive); Charcot Marie Tooth disease, type 4A, 214400; Charcot Marie Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth, Intermediate (Dominant) to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Intellectual disability v3.1537 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth; disease, axonal, with vocal cord paresis, 607706; Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, recessive; intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Mitochondrial disorders v2.97 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, axonal, type 2K; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, type 4A to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Hereditary neuropathy v1.445 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease, axonal, type 2K, 607831; Charcot Marie Tooth disease, type 4A, 214400; Charcot-Marie-Tooth, Intermediate (Dominant); Charcot Marie Tooth disease, type 4A, 214400; Charcot Marie Tooth disease, recessive intermediate, A, 608340; Charcot Marie Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth, Intermediate (Dominant); Charcot-Marie-Tooth with Vocal Cord Paresis (recessive); Charcot Marie Tooth disease, recessive intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Inborn errors of metabolism v2.240 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, type 4A; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, axonal, type 2K to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Possible mitochondrial disorder - nuclear genes v1.71 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, recessive intermediate, A, 608340; Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, 607706 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Undiagnosed metabolic disorders v1.522 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, axonal, type 2K; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, type 4A to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Adult solid tumours cancer susceptibility v2.19 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Lynch syndrome to Colorectal cancer, hereditary nonpolyposis, type 8, OMIM:613244
GI tract tumours v1.19 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Gastrointestinal and Colorectal Cancer; High Risk Colorectal Cancer to Colorectal cancer, hereditary nonpolyposis, type 8, OMIM:613244
Adult solid tumours for rare disease v1.32 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Lynch syndrome to Colorectal cancer, hereditary nonpolyposis, type 8, OMIM:613244
COVID-19 research v1.122 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Primary immunodeficiency v2.542 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Gastrointestinal epithelial barrier disorders v1.72 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital 613217; Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8, 613244; Diarrhea 5, with tufting enteropathy, congenital, 613217 to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Infantile enterocolitis & monogenic inflammatory bowel disease v1.38 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital 613217 to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Hereditary neuropathy NOT PMP22 copy number v1.90 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Hereditary neuropathy v1.444 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Paroxysmal central nervous system disorders v1.44 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Neuropathy, Hereditary Sensory and Autonomic, Type III; Familial dysautonomia; Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Pain syndromes v1.12 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Familial dysautonomia; NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Familial dysautonomia v1.17 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Familial Dysautonomia; Neuropathy, hereditary sensory and autonomic, type 3; Riley-Day Syndrome 223900 to Dysautonomia, familial, OMIM:223900
Childhood solid tumours cancer susceptibility v1.19 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Paediatric medulloblastoma Sonic Hedgehog subtype to Medulloblastoma, OMIM:155255
Tumour predisposition - childhood onset v2.31 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Medulloblastoma predisposition to Medulloblastoma, OMIM:155255
Palmoplantar keratodermas v1.13 CDSN Arina Puzriakova Tag Q2_22_rating tag was added to gene: CDSN.
Tag Q2_22_expert_review tag was added to gene: CDSN.
Palmoplantar keratodermas v1.13 CDSN Arina Puzriakova commented on gene: CDSN
Peeling skin syndrome v1.4 CDSN Arina Puzriakova Phenotypes for gene: CDSN were changed from Peeling skin syndrome 1, 270300; PSS1; OMIM:#270300; Peeling skin HP:0040189; Pruritus HP:0000989; Allergy HP:0012393; Increased IgE level HP:0003212; Generalised erythroderma HP:0001019; erythema HP:0010783; Hyperkeratosis HP:0000962. to Peeling skin syndrome 1, OMIM:270300; Peeling skin HP:0040189; Pruritus HP:0000989; Allergy HP:0012393; Increased IgE level HP:0003212; Generalised erythroderma HP:0001019; erythema HP:0010783; Hyperkeratosis HP:0000962.
Intellectual disability v3.1536 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Gene2Phenotype confirmed gene with ID HPO to Fanconi anemia, complementation group J, OMIM:609054
Growth failure in early childhood v1.103 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054; 609054 Fanconi anemia, complementation group J to Fanconi anemia, complementation group J, OMIM:609054
Fetal anomalies v1.849 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from FANCONI ANEMIA, COMPLEMENTATION GROUP J to Fanconi anemia, complementation group J, OMIM:609054
Confirmed Fanconi anaemia or Bloom syndrome v1.16 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from 609054 Fanconi anemia, complementation group J; Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Severe microcephaly v2.296 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Haematological malignancies cancer susceptibility v2.26 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Class: BM failure FA, (typ AR); AML; leukaemia; breast; Fanconi anaemia J; breast cancer susceptiblity; MDS; Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer, Squamous cell carcinoma oral, GI, vulvar to Fanconi anemia, complementation group J, OMIM:609054
Childhood solid tumours cancer susceptibility v1.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J 609054 to Fanconi anemia, complementation group J, OMIM:609054
Cytopenias and congenital anaemias v1.103 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J 609054 to Fanconi anemia, complementation group J, OMIM:609054
Pigmentary skin disorders v1.49 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from FANCJ; FANCONI ANEMIA, COMPLEMENTATION GROUP J to Fanconi anemia, complementation group J, OMIM:609054
Limb disorders v2.77 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Radial Ray abnormality; Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054; Radial ray abnormality
Tumour predisposition - childhood onset v2.30 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054; Fanconi anemia, complementation group J, 609054; Fanconi Anaemia; ?Breast cancer, early-onset, 114480; Fanconi Anemia to Fanconi anemia, complementation group J, OMIM:609054
COVID-19 research v1.121 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Neurofibromatosis Type 1 v1.29 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from ?Breast cancer, early-onset, 114480; Fanconi anemia, complementation group J, 609054; Fanconi Anemia; Fanconi Anaemia to Fanconi anemia, complementation group J, OMIM:609054
Haematological malignancies for rare disease v1.10 BRIP1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: "Class: BM failure FA, (typ AR);AML; leukaemia; breast;Fanconi anaemia J; breast cancer susceptiblity;MDS; Leukaemia;Bone marrow failure;Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer, Squamous cell carcinoma oral, GI, vulvar"
Haematological malignancies for rare disease v1.10 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Class: BM failure FA, (typ AR); AML; leukaemia; breast; Fanconi anaemia J; breast cancer susceptiblity; MDS; Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer, Squamous cell carcinoma oral, GI, vulvar to Fanconi anemia, complementation group J, OMIM:609054
Radial dysplasia v1.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Adult solid tumours cancer susceptibility v2.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from predisposition to ovarian cancer to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Adult solid tumours for rare disease v1.31 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from predisposition to ovarian cancer to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Ovarian cancer pertinent cancer susceptibility v1.9 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Familial breast cancer v1.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from ?Breast cancer, early-onset, 114480; Fanconi anemia, complementation group J, 609054; Breast and Ovarian Cancer; Breast Cancer to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Osteogenesis imperfecta v2.45 P4HB Eleanor Williams Tag Q2_22_MOI tag was added to gene: P4HB.
Osteogenesis imperfecta v2.45 P4HB Eleanor Williams Phenotypes for gene: P4HB were changed from Cole-Carpenter Syndrome; Osteogenesis Imperfecta; Cole Carpenter syndrome to Cole-Carpenter syndrome 1, OMIM:112240; Cole-Carpenter syndrome 1, MONDO:000720
Osteogenesis imperfecta v2.44 P4HB Eleanor Williams Added comment: Comment on mode of inheritance: Cole-Carpenter syndrome 1 is due to heterozygous variants in P4HB and so the mode of inheritance should be changed to monoallelic at the next review.
Osteogenesis imperfecta v2.44 P4HB Eleanor Williams Mode of inheritance for gene: P4HB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis v2.22 CFHR5 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic just now, but only monoallelic cases confirmed so recommending a change to this mode of inheritance.
Membranoproliferative glomerulonephritis v2.22 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 v2.21 CFHR5 Eleanor Williams Tag Q2_22_MOI tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis v2.21 CFHR5 Eleanor Williams reviewed gene: CFHR5: Rating: ; Mode of pathogenicity: None; Publications: 20800271, 22503529, 23402027, 24334459, 24067434, 34566977; Phenotypes: Nephropathy due to CFHR5 deficiency, OMIM:614809; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood solid tumours cancer susceptibility v1.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Hereditary Breast and Ovarian Cancer to Fanconi anemia, complementation group D1, OMIM:605724; Wilms tumor, OMIM:194070; {Glioblastoma 3}, OMIM:613029; {Medulloblastoma}, OMIM:155255
Tumour predisposition - childhood onset v2.29 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Wilms tumor, 194070; Fanconi Anaemia; {Breast cancer, male, susceptibility to}, 114480; Prostate cancer, 176807; {Medulloblastoma}, 155255; {Glioblastoma 3}, 613029; Fanconi Anemia; Hereditary Breast and Ovarian Cancer; Fanconi anemia, complementation group D1, 605724; {Breast-ovarian cancer, familial, 2}, 612555; Pancreatic cancer, 613347 to Fanconi anemia, complementation group D1, OMIM:605724; Wilms tumor, OMIM:194070; {Glioblastoma 3}, OMIM:613029; {Medulloblastoma}, OMIM:155255
Primary immunodeficiency v2.541 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type D1 to Fanconi anemia, complementation group D1, OMIM:605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
COVID-19 research v1.120 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type D1 to Fanconi anemia, complementation group D1, OMIM:605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
Intellectual disability v3.1535 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1: FANCD1 OMIM: 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Growth failure in early childhood v1.102 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; 605724 Fanconi anemia, complementation group D1 to Fanconi anemia, complementation group D1, OMIM:605724
Confirmed Fanconi anaemia or Bloom syndrome v1.15 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from 605724 Fanconi anemia, complementation group D1; Fanconi anemia, complementation group D1, 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Severe microcephaly v2.295 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724 (Microcephaly) to Fanconi anemia, complementation group D1, OMIM:605724
Haematological malignancies cancer susceptibility v2.25 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; breast, ovarian, pancreatic, leukaemia (FANCB, FANCD1); hereditary breast, ovarian cancer; MDS; AML, Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer ,Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group D1, OMIM:605724
Cytopenias and congenital anaemias v1.102 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Pigmentary skin disorders v1.48 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from FANCD1; FANCONI ANEMIA, COMPLEMENTATION GROUP D1 to Fanconi anemia, complementation group D1, OMIM:605724
Limb disorders v2.76 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; Radial Ray abnormality to Fanconi anemia, complementation group D1, OMIM:605724
Neurofibromatosis Type 1 v1.28 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from {Breast-ovarian cancer, familial, 2}, 612555; Fanconi anemia, complementation group D1, 605724; Prostate cancer, 176807; {Breast cancer, male, susceptibility to}, 114480; Wilms tumor, 194070; {Medulloblastoma}, 155255; {Glioblastoma 3}, 613029; Pancreatic cancer, 613347; {Glioblastoma 3},; Fanconi Anemia; Fanconi Anaemia to Fanconi anemia, complementation group D1, OMIM:605724
Haematological malignancies for rare disease v1.9 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; breast, ovarian, pancreatic, leukaemia (FANCB, FANCD1); hereditary breast, ovarian cancer; MDS; AML, Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer ,Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group D1, OMIM:605724
Radial dysplasia v1.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Prostate cancer pertinent cancer susceptibility v1.2 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Prostate cancer to {Prostate cancer}, OMIM:176807
Familial prostate cancer v1.3 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from male breast cancer and prostate cancer; {Prostate cancer} 176807 to {Prostate cancer}, OMIM:176807
Additional findings health related - CNV analysis adult specific v1.2 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; Adult only
Additional findings health related - adult specific v1.2 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; Adult only
Adult solid tumours cancer susceptibility v2.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; {Prostate cancer}, OMIM:176807
Adult solid tumours for rare disease v1.30 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; {Prostate cancer}, OMIM:176807
Ovarian cancer pertinent cancer susceptibility v1.8 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Ovarian cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555
Breast cancer pertinent cancer susceptibility v1.6 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Breast cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480
Additional findings health related v0.114 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Breast and ovarian cancer predisposition; Adult only to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; Adult only
Familial breast cancer v1.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from {Breast-ovarian cancer, familial, 2}, 612555; Fanconi anemia, complementation group D1, 605724; Prostate cancer, 176807; {Breast cancer, male, susceptibility to}, 114480; Wilms tumor, 194070; {Medulloblastoma}, 155255; {Glioblastoma 3},; Hereditary Breast and Ovarian Cancer ; Hereditary Breast and Ovarian Cancer Syndrome; Breast and Ovarian Cancer; High Risk Breast Cancer ; Breast cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480
Primary immunodeficiency v2.540 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia, complementation group S, 617883; normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type S to Fanconi anemia, complementation group S, OMIM:617883; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
COVID-19 research v1.119 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia, complementation group S, 617883; normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type S to Fanconi anemia, complementation group S, OMIM:617883; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
Confirmed Fanconi anaemia or Bloom syndrome v1.14 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia; 617883 Fanconi anemia, complementation group S to Fanconi anemia, complementation group S, OMIM:617883
Haematological malignancies cancer susceptibility v2.24 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group S, OMIM:617883
Cytopenias and congenital anaemias v1.101 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia to Fanconi anemia, complementation group S, OMIM:617883
Pigmentary skin disorders v1.47 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from FANCS; FANCONI ANEMIA, COMPLEMENTATION GROUP S to Fanconi anemia, complementation group S, OMIM:617883
Haematological malignancies for rare disease v1.8 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group S, OMIM:617883
Ovarian cancer pertinent cancer susceptibility v1.7 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic germline BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Ovarian cancer pertinent cancer susceptibility v1.7 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Breast cancer pertinent cancer susceptibility v1.5 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Ovarian cancer pertinent cancer susceptibility v1.6 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Breast cancer pertinent cancer susceptibility v1.5 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic germline BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Breast cancer pertinent cancer susceptibility v1.5 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited bleeding disorders v1.166 F12 Arina Puzriakova Tag watchlist was removed from gene: F12.
Tag watchlist_moi tag was added to gene: F12.
Familial breast cancer v1.16 BRCA1 Arina Puzriakova Tag watchlist_moi tag was added to gene: BRCA1.
Inherited breast cancer and ovarian cancer v0.17 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic germline BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Inherited breast cancer and ovarian cancer v0.17 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited breast cancer and ovarian cancer v0.16 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Inherited ovarian cancer (without breast cancer) v2.25 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Inherited ovarian cancer (without breast cancer) v2.25 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375). There are at least two unrelated individuals in literature who were diagnosed with ovarian carcinoma in association with biallelic germline BRCA1 variants.

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Inherited ovarian cancer (without breast cancer) v2.25 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Additional findings health related - CNV analysis adult specific v1.1 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Adult only
Additional findings health related - adult specific v1.1 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Adult only
Adult solid tumours for rare disease v1.29 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'monoallelic' to 'both mono- and biallelic' to align with the MOI set on the GMS Adult solid tumours cancer susceptibility (v2.2) panel. Although more rare, biallelic BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).
Adult solid tumours for rare disease v1.29 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult solid tumours for rare disease v1.28 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Fanconi anemia, complementation group S, OMIM:617883
Adult solid tumours cancer susceptibility v2.16 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Fanconi anemia, complementation group S, OMIM:617883
Childhood solid tumours cancer susceptibility v1.16 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Tumour predisposition - childhood onset v2.28 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Ovarian cancer pertinent cancer susceptibility v1.6 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Ovarian cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Breast cancer pertinent cancer susceptibility v1.4 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Breast cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Additional findings health related v0.113 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Breast and ovarian cancer predisposition; Adult only to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Breast and ovarian cancer predisposition; Adult only
Familial breast cancer v1.16 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from {Breast-ovarian cancer, familial, 1}, 604370; {Pancreatic cancer, susceptibility to, 4}, 614320; Hereditary Breast and Ovarian Cancer ; Hereditary Breast and Ovarian Cancer Syndrome; Breast and Ovarian Cancer; High Risk Breast Cancer ; Breast cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Familial prostate cancer v1.2 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from to Prostate cancer, MONDO:0008315
Inherited bleeding disorders v1.166 F12 Arina Puzriakova Tag watchlist tag was added to gene: F12.
Inherited bleeding disorders v1.166 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Coagulaton disorder; Angioedema, hereditary, type 3 (AD); Angioedema, hereditary, type III; Factor 12 deficiency (AR); Factor XII deficiency to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000
Bleeding and platelet disorders v1.37 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from 234000 Factor XII deficiency; 234000 Factor XII deficiency, hereditary Angioedema type III; 610618 Hereditary Angioedema type III to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000
Bleeding and platelet disorders v1.36 F12 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: F12.
Tag Q2_22_phenotype tag was added to gene: F12.
Tag Q2_22_expert_review tag was added to gene: F12.
Bleeding and platelet disorders v1.36 F12 Arina Puzriakova changed review comment from: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only or should be demoted on this panel altogether.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.; to: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only or whether this gene should be demoted on this panel altogether.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.
Bleeding and platelet disorders v1.36 F12 Arina Puzriakova changed review comment from: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.; to: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only or should be demoted on this panel altogether.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.
Vascular skin disorders v1.49 F12 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: F12.
Tag Q2_22_expert_review tag was added to gene: F12.
Vascular skin disorders v1.49 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Angioedema, hereditary, type III, OMIM:610618 to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000
Intellectual disability v3.1534 ZBTB7A Konstantinos Varvagiannis gene: ZBTB7A was added
gene: ZBTB7A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7A were set to 31645653; 34515416
Phenotypes for gene: ZBTB7A were set to 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
Penetrance for gene: ZBTB7A were set to unknown
Review for gene: ZBTB7A was set to AMBER
Added comment: Monoallelic pathogenic ZBTB7A variants cause Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (#619769).
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Ohishi et al (2020 - PMID: 31645653) described the phenotype of a 6y5m-old male harboring a heterozygous, de novo ZBTB7A missense variant. Features included macrocephaly, mild intellectual disability (tIQ 65) and sleep apnea. Available hemoglobin levels (in the 1st month) supported high Hb and HbF levels. Other features included PDA and an umbilical hernia.

Initial investigations incl. karyotype and CMA were normal.

The ZBTB7A variant (NM_015898.3:c.1152C>G / p.Cys384Tyr) was identified following trio WES with a list of additional findings (in suppl.) not explaining the phenotype. This SNV, confirmed by Sanger sequencing, was absent from public db with several in silico predictions in favor of a deleterious effect.

ZBTB7A on 19p encodes zinc finger- and BTB domain-containing protein 7 (or Pokemon).

The authors performed a review of 19p13.3 microdeletion cases supporting a minimum region of overlap spanning PIAS4, ZBTB7A and MAP2K2 and common features of DD and ID, macrocephaly with prominent forehead, sleep apnea. The authors argue that loss of ZBTB7A explains part of - but probably not all - features of 19p13.3 microdeletions.

ZBTB7A is known to repress expression of HBG1 and HBG2 (γ-globin), with the few available HbF patient measurements in line with this role.

Based on the structure of the protein, Cys384 (along with 3 other residues) forms a coordinate bond with the Zn+2 ion, this bond predicted to be disrupted by Tyr. Further they favor a dominant negative effect given that ZBTB7A protein is known to form dimer via interaction at the BTB domain [hetero (variant+wt) and homodimers (variant+variant) having compromised function]. To support this notion, 3 previously reported somatic variants within the zinc-finger domain have been shown to exert a dominant-negative effect (PMID cited: 26455326).
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In a collaborative study, von der Lippe et al (2022 - PMID: 34515416) identified 12 additional individuals (from 10 families) harboring monoallelic ZBTB7A missense/pLoF variants most commonly as de novo events.

The authors describe a consistent phenotype with motor (9/11) and speech delay (9/12), cognitive impairment/ID (12/12 - commonly mild, ranged from specific learning difficulties to severe ID), macrocephaly (>90%le in 11/12, >97% in 7/12), lymphoid hypertrophy of pharyngeal tissue/adenoid overgrowth (12/12), sleep apnea (9/12). Autistic features were observed in 7/12. Other phenotypes included frequent upper airway infections (10/11), weight above 97th percentile (7/11). HbF levels were elevated in 4/5 individuals with available measurements (range: 2.2% to 11.2% - ref. for subjects above 6m of age : <2% ). Other hematological issues were observed in few individuals (abn. monocyte/neutrophil counts in 3-4). Cardiovascular issues were reported in 4 (2 fam). 3 subjects had umbilical hernia. There was no common dysmorphic feature.

Various initial investigations were normal or did not appear to explain the NDD phenotype and incl. standard karyotype, CMA, targeted testing for genes/disorders previously considered (PTEN, FMR1, NSD1, BWS and PWS methylation studies, CFTR, etc). One male had a maternally inherited chrX dup not thought to explain his complex phenotype, while another had a concurrent diagnosis of thalassemia.

Individuals were investigated with singleton (or trio) WES. Of note some individuals were DDD study participants.

8 had de novo ZBTB7A variants, incl. one who harbored 2 de novo missense SNVs several residues apart. 2 sibs had inherited a fs variant from their affected parent. For the latter as well as for another subject parental samples were unavailable.

There were no other variants of interest upon exome analysis.

5 different missense, 2 nonsense and 3 fs variants were identified with pLoF all predicted to lead to NMD.

All variants were absent from gnomAD (pLI of 0.96, LOEUF 0.33 and missense Z-score of 4.04) which lists one individual with htz LoF, likely not an artifact.

Given this individual (and the familial case) the authors discuss on the mild phenotype and/or eventual reduced penetrance or underdiagnosis of the disorder.

There was no difference in severity between those with missense/truncating variants.

ZBTB7A transcription factor (or pokemon or lymphoma/leukemia-related factor) is widely expressed. It is involved in several activities being among others required to block Notch signaling which in turn drives T-cell at the expense of B-cell development. Notch pathway activation has been demonstrated in Zbtba7 ko mouse models. Finally, the authors discuss the role of notch signaling in thymus and the nervous system, as well as that ZBTB7A up/down-regulation known to repress/increase respectively HbF expression (several refs in text).
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MGI (1335091) for Zbtb7a : "Mice homozygous for a knock-out allele die around E16.5 due to anemia and exhibit a cell autonomous defect in early B cell development". (Phenotypes from nervous system not commented on).
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Apart from OMIM (#619769), ZBTB7A is included in the DD panel of G2P (ZBTB7A-associated developmental disorder / monoallelic_autosomal / absent gene product / confidence limited) as well as among the primary ID genes in SysID. In PanelApp Australia the gene is incl. with green rating in the ID and Macrocephaly gene panels.
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Consider inclusion with amber or green rating (several individuals/families/variants, highly consistent phenotype, overlap with 19p microdeletions || variant effect not studied, animal models supporting contribution of the gene to the phenotype though no data on associated NDD ones).

Please also consider inclusion in other relevant panels (macrocephaly, lymphatic disorders, ASD, etc).
Sources: Literature, Other
Genetic epilepsy syndromes v2.504 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 33057194
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to AMBER
Added comment: At least 12 individuals with NDD due to monoallelic missense/pLoF ATP2B1 variants have been reported to date. Seizures were observed in 5 of them.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with amber rating.
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Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Intellectual disability v3.1534 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 35358416
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to GREEN
Added comment: Monoallelic missense/pLoF ATP2B1 variants have been reported in 12 unrelated individuals with DD/ID making this gene relevant to the current panel.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with green (rather than amber) rating.
---
Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Retinal disorders v2.251 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595; 29220678; 21937992
Retinal disorders v2.250 PEX6 Sarah Leigh commented on gene: PEX6: Retinal involvement is mentioned in Peroxisome biogenesis disorder 4B (OMIM:614863)(PMID:21937992; 22871920).
Retinal disorders v2.250 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595; 29220678
Retinal disorders v2.249 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Retinal disorders v2.248 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.248 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Heimler syndrome 2, OMIM:616617, MONDO:0014709 to Heimler syndrome 2, OMIM:616617; MONDO:0014709; Peroxisome biogenesis disorder 4B, OMIM:614863
Retinal disorders v2.247 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595
Retinal disorders v2.246 PEX6 Sarah Leigh Added comment: 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.
Retinal disorders v2.246 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.245 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Arthrogryposis v3.158 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Arthrogryposis v3.157 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: Arthrogryposis maybe over looked in patients with Peroxisome biogenesis disorder 4A (Zellweger) (OMIM:614862) and Peroxisome biogenesis disorder 4B (OMIM:6148630), as these conditions are characterized by a severe phenotype and premature death in some cases. If this is the case, for Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) have 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Arthrogryposis v3.157 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Arthrogryposis v3.157 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Arthrogryposis v3.156 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 20301621
Arthrogryposis v3.155 PEX6 Sarah Leigh Added comment: 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.
Arthrogryposis v3.155 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.233 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
White matter disorders and cerebral calcification - narrow panel v1.232 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4B 614863; Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
White matter disorders and cerebral calcification - narrow panel v1.231 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 25655951
White matter disorders and cerebral calcification - narrow panel v1.230 PEX6 Sarah Leigh Added comment: 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.
White matter disorders and cerebral calcification - narrow panel v1.230 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.229 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
White matter disorders and cerebral calcification - narrow panel v1.229 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.521 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Undiagnosed metabolic disorders v1.520 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Disorders of peroxisome biogenesis; Peroxisome biogenesis disorder 4A (Zellweger) 614862; Peroxisome biogenesis disorder 4B 614863 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Undiagnosed metabolic disorders v1.519 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308
Undiagnosed metabolic disorders v1.518 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.
Undiagnosed metabolic disorders v1.518 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.517 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Peroxisomal disorders v1.19 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Peroxisomal disorders v1.18 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Peroxisomal disorders v1.18 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Peroxisomal disorders v1.17 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.
Peroxisomal disorders v1.17 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Malformations of cortical development v2.141 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Malformations of cortical development v2.140 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Malformations of cortical development v2.140 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Malformations of cortical development v2.140 PEX6 Sarah Leigh Added comment: 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.
Malformations of cortical development v2.140 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.139 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Disorders of peroxisome biogenesis; Peroxisome biogenesis disorder 4A (Zellweger), 614862; Peroxisome biogenesis disorder 4B, 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Malformations of cortical development v2.138 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308
Intellectual disability v3.1534 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Intellectual disability v3.1533 PEX6 Sarah Leigh Added comment: 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.
Intellectual disability v3.1533 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1532 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger), 614862Peroxisome biogenesis disorder 4B, 614863; ZELLWEGER SYNDROME (ZWS) to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Intellectual disability v3.1531 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Intellectual disability v3.1530 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Intellectual disability v3.1530 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inborn errors of metabolism v2.239 PEX6 Sarah Leigh Mode of pathogenicity for gene PEX6 was changed from to Other
Penetrance for gene PEX6 was set from to None
Inborn errors of metabolism v2.238 PEX6 Sarah Leigh commented on gene: PEX6: 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).
Inborn errors of metabolism v2.238 PEX6 Sarah Leigh Added comment: 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.
Inborn errors of metabolism v2.238 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.237 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Hereditary ataxia - adult onset v2.154 PEX6 Sarah Leigh Mode of pathogenicity for gene PEX6 was changed from to Other
Penetrance for gene PEX6 was set from to None
Hereditary ataxia - adult onset v2.153 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia - adult onset v2.153 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Hereditary ataxia - adult onset v2.153 PEX6 Sarah Leigh Added comment: 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.
Hereditary ataxia - adult onset v2.153 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia - adult onset v2.152 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A, 614862; Peroxisome biogenesis disorder 4B, 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Hereditary ataxia - adult onset v2.151 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Fetal hydrops v1.55 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Fetal hydrops v1.54 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal hydrops v1.54 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 20033294; 23137060
Fetal hydrops v1.53 PEX6 Sarah Leigh Added comment: 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.
Fetal hydrops v1.53 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.52 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Fetal hydrops v1.52 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Zellweger, peroxisome biogenesis disorder 4A, 4B; Peroxisome biogenesis disorder 4A (Zellweger), 614862; Peroxisome biogenesis disorder 4B, 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Fetal hydrops v1.51 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
DDG2P v2.69 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Fetal anomalies v1.848 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Fetal anomalies v1.847 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 pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.847 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from PEROXISOME BIOGENESIS DISORDER COMPLEMENTATION GROUP 4; ZELLWEGER SYNDROME to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Fetal anomalies v1.846 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Fetal anomalies v1.845 PEX6 Sarah Leigh Added comment: 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.
Fetal anomalies v1.845 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.844 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
DDG2P v2.68 PEX6 Sarah Leigh changed review comment from: 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).; to: 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).
DDG2P v2.68 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
DDG2P v2.67 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 pathogenicity: Other; Changed phenotypes to: 29220678; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.67 PEX6 Sarah Leigh Added comment: 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. Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
DDG2P v2.67 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.66 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
DDG2P v2.66 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from ZELLWEGER SYNDROME 214100; PEROXISOME BIOGENESIS DISORDER COMPLEMENTATION GROUP 4 601498 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Amelogenesis imperfecta v2.19 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Amelogenesis imperfecta v2.18 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 pathogenicity: Other; Changed publications to: 29220678
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Added comment: 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. Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.17 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 26387595; 16530715
Amelogenesis imperfecta v2.16 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: The review by Claire Smith (University of Leeds)(below), states that amelogenesis imperfecta maybe over looked in patients with Peroxisome biogenesis disorder 4A (Zellweger) (OMIM:614862) and Peroxisome biogenesis disorder 4B (OMIM:6148630), as these conditions are characterized by a severe phenotype and premature death in some cases. With this in mind the Peroxisome biogenesis disorder 4B (OMIM:614863) could be relevant to this panel and such the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in order to detect variants resulting in allelic expression imbalance and dominant-negative effect (PMID: 29220678).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.16 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Heimler syndrome 2, OMIM:616617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cataracts v2.104 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger); Confirmed DD gene for ZELLWEGER SYNDROME; Peroxisome biogenesis disorder to Heimler syndrome 2, OMIM:616617
Cataracts v2.103 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Cataracts v2.102 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: None; Publications: 26387595; Phenotypes: Heimler syndrome 2 OMIM:616617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.157 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Inherited white matter disorders v1.156 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: 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.
Inherited white matter disorders v1.156 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited white matter disorders v1.155 PEX6 Sarah Leigh Mode of pathogenicity for gene: PEX6 was changed from None to Other
Inherited white matter disorders v1.154 PEX6 Sarah Leigh Added comment: Comment on mode of pathogenicity: Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678).
Inherited white matter disorders v1.154 PEX6 Sarah Leigh Mode of pathogenicity for gene: PEX6 was changed from to None
Inherited white matter disorders v1.153 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862; Peroxisome biogenesis disorder 4B 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Inherited white matter disorders v1.152 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 25655951
White matter disorders and cerebral calcification - narrow panel v1.229 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.229 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.228 PNPT1 Arina Puzriakova gene: PNPT1 was added
gene: PNPT1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Q1_22_rating tags were added to gene: PNPT1.
Mode of inheritance for gene: PNPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPT1 were set to 28594066; 30046113; 33199448
Phenotypes for gene: PNPT1 were set to Combined oxidative phosphorylation deficiency 13, OMIM:614932
Review for gene: PNPT1 was set to GREEN
Added comment: White matter abnormalities can be observed in some patients with PNPT1-related mitochondrial disease caused by biallelic variants. Overall at 6 least unrelated cases reported in literature with diminished white matter and/or delayed myelination which is sufficient to justify a Green rating on this panel.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.225 PNPT1 Arina Puzriakova edited their review of gene: PNPT1: Changed rating: GREEN
Childhood onset dystonia or chorea or related movement disorder v1.225 PNPT1 Arina Puzriakova Publications for gene: PNPT1 were set to 23084291; 33199448
Primary ciliary disorders v1.40 XPNPEP3 Sarah Leigh commented on gene: XPNPEP3: Helen Brittain (GEL Clinical Fellow) agrees with the review from Ian Berry (below) that this gene is not relevant for Primary ciliary disorders. XPNPEP3 is recommended to be green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/XPNPEP3/#!review).
Childhood onset dystonia or chorea or related movement disorder v1.224 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.224 PNPT1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate this gene as Green at the next GMS review.
Childhood onset dystonia or chorea or related movement disorder v1.224 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.223 PNPT1 Arina Puzriakova Publications for gene: PNPT1 were set to
Childhood onset dystonia or chorea or related movement disorder v1.222 PNPT1 Arina Puzriakova Tag Q1_22_rating tag was added to gene: PNPT1.
Childhood onset dystonia or chorea or related movement disorder v1.222 PNPT1 Arina Puzriakova reviewed gene: PNPT1: Rating: ; Mode of pathogenicity: None; Publications: 33199448; Phenotypes: Combined oxidative phosphorylation deficiency 13, OMIM:614932; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.222 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Dystonia
Adult onset movement disorder v1.168 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Dystonia to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Dystonia
Hearing loss v2.238 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934
Mitochondrial disorders v2.96 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; respiratory chain disorder; hearing loss to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Inborn errors of metabolism v2.237 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Deafness, autosomal recessive 70, 614934; Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; respiratory chain disorder; hearing loss; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Possible mitochondrial disorder - nuclear genes v1.70 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Deafness, autosomal recessive 70, 614934; Combined oxidative phosphorylation deficiency 13, 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Undiagnosed metabolic disorders v1.517 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; respiratory chain disorder; hearing loss to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Intellectual disability v3.1530 MAN2C1 Konstantinos Varvagiannis gene: MAN2C1 was added
gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly
Penetrance for gene: MAN2C1 were set to unknown
Review for gene: MAN2C1 was set to GREEN
Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder.
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Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam).

While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4).

All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs).

There were no putative pathogenic variants in known disease genes.

MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation.

Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3]

Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect.

For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg.

Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT.

Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg.

In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects.

The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation.

Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides.
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G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels.

Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals).

Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc).
Sources: Literature, Other
Intellectual disability v3.1530 TLK2 Arina Puzriakova Publications for gene: TLK2 were set to 27479843; https://doi.org/10.1016/j.ajhg.2018.04.014
Craniosynostosis v2.68 SIX1 Arina Puzriakova Publications for gene: SIX1 were set to
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova commented on gene: ZNF423: There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova reviewed gene: ZNF423: Rating: ; Mode of pathogenicity: None; Publications: 22863007, 32925911, 33323469; Phenotypes: Joubert syndrome 19, OMIM:614844, Nephronophthisis 14, OMIM:614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: ZNF423.
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova Classified gene: ZNF423 as Amber List (moderate evidence)
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova Gene: znf423 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.40 ZNF423 Arina Puzriakova Publications for gene: ZNF423 were set to
Neurological ciliopathies v1.31 ZNF423 Arina Puzriakova Publications for gene: ZNF423 were set to
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: ZNF423.
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova commented on gene: ZNF423: There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova reviewed gene: ZNF423: Rating: ; Mode of pathogenicity: None; Publications: 22863007, 32925911, 33323469; Phenotypes: Joubert syndrome 19, OMIM:614844, Nephronophthisis 14, OMIM:614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.30 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Rare multisystem ciliopathy disorders v1.160 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Joubert syndrome 19, 614844; Nephronophthisis 14, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Childhood onset dystonia or chorea or related movement disorder v1.221 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Joubert syndrome 19; Nephronophthisis 14; Nephronophthisis 14, 614844; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Unexplained paediatric onset end-stage renal disease v1.34 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Ciliopathy genes associated with cystic kidney disease to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Cystic kidney disease v2.39 ZNF423 Arina Puzriakova Mode of inheritance for gene: ZNF423 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v1.19 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Joubert syndrome 19 MIM 614844; Nephronopthisis 14 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Cystic kidney disease v2.38 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Ciliopathy genes associated with cystic kidney disease to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Unexplained kidney failure in young people v1.106 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Ciliopathy genes associated with cystic kidney disease to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Renal ciliopathies v1.63 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Renal ciliopathies v1.62 ZNF423 Arina Puzriakova Publications for gene: ZNF423 were set to 22863007
Renal ciliopathies v1.61 ZNF423 Arina Puzriakova commented on gene: ZNF423: There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.
Renal ciliopathies v1.61 ZNF423 Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: ZNF423.
Genetic epilepsy syndromes v2.504 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Genetic epilepsy syndromes. Sources: Literature,Other
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 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
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Intellectual disability v3.1529 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other
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 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
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Renal ciliopathies v1.61 ZNF423 Arina Puzriakova reviewed gene: ZNF423: Rating: ; Mode of pathogenicity: None; Publications: 22863007, 32925911, 33323469; Phenotypes: Joubert syndrome 19, OMIM:614844, Nephronophthisis 14, OMIM:614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.190 ANO5 Sarah Leigh Tag Q1_22_MOI tag was added to gene: ANO5.
DDG2P v2.65 ANO5 Sarah Leigh reviewed gene: ANO5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.65 ALPL Sarah Leigh reviewed gene: ALPL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cystic kidney disease v2.37 ALG8 Sarah Leigh Publications for gene: ALG8 were set to 30135240; 28375157
Cystic kidney disease v2.36 ALG8 Sarah Leigh reviewed gene: ALG8: Rating: ; Mode of pathogenicity: None; Publications: 15235028; Phenotypes: ; Mode of inheritance: None
Polycystic liver disease interim v1.23 ALG8 Sarah Leigh reviewed gene: ALG8: Rating: ; Mode of pathogenicity: None; Publications: 15235028; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1529 ALG8 Sarah Leigh Publications for gene: ALG8 were set to 0
Inborn errors of metabolism v2.236 SPTLC1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SPTLC1.
Inborn errors of metabolism v2.236 SPTLC1 Sarah Leigh Added comment: Comment on mode of inheritance: There is no data to support that homozygous variants of SPTLC1 are associated with Neuropathy, hereditary sensory and autonomic, type IA, OMIM:162400. Therefore the MOI for this gene should be MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inborn errors of metabolism v2.236 SPTLC1 Sarah Leigh Mode of inheritance for gene: SPTLC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.516 SPTLC1 Sarah Leigh Mode of inheritance for gene: SPTLC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.515 SPTLC1 Sarah Leigh Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Inborn errors of metabolism v2.235 SPTLC1 Sarah Leigh Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Inborn errors of metabolism v2.234 SPTLC1 Sarah Leigh Deleted their comment
Inborn errors of metabolism v2.234 SPTLC1 Sarah Leigh Deleted their comment
Inborn errors of metabolism v2.234 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Intellectual disability v3.1528 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36, 615286; MRT36 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Genetic epilepsy syndromes v2.504 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36 615286 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Extreme early-onset hypertension v1.15 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Neuropathy, hereditary sensory and autonomic, type II, 201300; Pseudohypoaldosteronism, type IIC, 614492 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300; Pseudohypoaldosteronism, type IIC, OMIM:614492
Renal tubulopathies v2.40 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Pseudohypoaldosteronism, type IIC, 614492 to Pseudohypoaldosteronism, type IIC, OMIM:614492
Hereditary neuropathy NOT PMP22 copy number v1.89 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory and autonomic, type II, 201300; Pseudohypoaldosteronism, type IIC, 614492 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Hereditary neuropathy v1.443 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Hereditary Sensory and Autonomic Neuropathy, Type II; Pseudohypoaldosteronism, type IIC, 614492; Hereditary Sensory and Autonomic Neuropathy, Type II ; Neuropathy, hereditary sensory and autonomic, type II, 201300; Pseudohypoaldosteronism, type IIC, 614492 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Paroxysmal central nervous system disorders v1.43 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from HSAN 2; Neuropathy, hereditary sensory and autonomic, type II, 201300; Hereditary sensory and autonomic neuropathy type IIA to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Familial dysautonomia v1.16 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Neuropathy, hereditary sensory and autonomic, type II 201300 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Pain syndromes v1.11 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Hereditary sensory and autonomic neuropathy type IIA; HSAN 2; Neuropathy, hereditary sensory and autonomic, type II, 201300 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Early onset dystonia v1.113 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Dystonia-1, torsion, OMIM:128100; Dystonic disorder, MONDO:0003441 to Dystonia-1, torsion, OMIM:128100; Arthrogryposis multiplex congenita 5, OMIM:618947
Childhood onset dystonia or chorea or related movement disorder v1.220 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Dystonia-1, torsion, OMIM:128100; Dystonic disorder, MONDO:0003441 to Dystonia-1, torsion, OMIM:128100; Arthrogryposis multiplex congenita 5, OMIM:618947
Early onset dystonia v1.112 TOR1A Arina Puzriakova Added comment: Comment on mode of inheritance: Dystonia association with monoallelic variants is well-established with multiple cases reported worldwide (OMIM:128100). Biallelic variants cause a more severe phenotype of congenital arthrogryposis (OMIM:618947) and movement impairments including dystonia are also common (PMIDs: 29053766, 30244176). For this reason the MOI was updated from 'monoallelic' only to 'both mono- and biallelic (biallelic more severe)'.
Early onset dystonia v1.112 TOR1A Arina Puzriakova Mode of inheritance for gene: TOR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.219 TOR1A Arina Puzriakova Publications for gene: TOR1A were set to 20301334; 11523564; 17503336; 20301665; 9288096; 16537570
Childhood onset dystonia or chorea or related movement disorder v1.218 TOR1A Arina Puzriakova Tag Q1_22_MOI tag was added to gene: TOR1A.
Childhood onset dystonia or chorea or related movement disorder v1.218 TOR1A Arina Puzriakova reviewed gene: TOR1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia-1, torsion, OMIM:128100, Arthrogryposis multiplex congenita 5, OMIM:618947; Mode of inheritance: None
Intellectual disability v3.1527 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal hematodiaphyseal syndrome, OMIM:231095 to Ghosal hematodiaphyseal syndrome, OMIM:231095
Intellectual disability v3.1527 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal hematodiaphyseal syndrome, 231095; ?Thromboxane synthase; deficiency, 614158 to Ghosal hematodiaphyseal syndrome, OMIM:231095
Inherited bleeding disorders v1.165 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal syndrome to Ghosal hematodiaphyseal syndrome, OMIM:231095; ?Thromboxane synthase deficiency, OMIM:614158; Bleeding disorder, platelet-type, 14, OMIM:614158
Bleeding and platelet disorders v1.36 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from 231095 Ghosal hematodiaphyseal syndrome; 614158 ?Thromboxane synthase deficiency; 614158 ?Thromboxane synthase deficiency, 231095 Ghosal hematodiaphyseal syndrome to Ghosal hematodiaphyseal syndrome, OMIM:231095; ?Thromboxane synthase deficiency, OMIM:614158; Bleeding disorder, platelet-type, 14, OMIM:614158
Hereditary ataxia - adult onset v2.150 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar Ataxia, Dominant; Autosomal recessive spinocerebellar ataxia 14, 615386; Spinocerebellar ataxia, autosomal recessive 14; Spinocerebellar ataxia 5; Spinocerebellar ataxia 5, 600224; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant); SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14 to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Neurodegenerative disorders - adult onset v2.269 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14; Spinocerebellar Ataxia, Dominant; Spinocerebellar ataxia, autosomal recessive 14; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant); Spinocerebellar ataxia 5 to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Cerebellar hypoplasia v1.62 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia 5 (AD); Spinocerebellar ataxia, autosomal recessive 14 (AR) to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Hereditary ataxia v1.300 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia 5; Spinocerebellar ataxia, autosomal recessive 14; Spinocerebellar Ataxia, Dominant; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant); SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14 to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Intellectual disability v3.1526 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia, autosomal recessive 14; MIM:615386; Developmental delay to Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova Tag Q2_21_MOI tag was added to gene: SLURP1.
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova reviewed gene: SLURP1: Rating: ; Mode of pathogenicity: None; Publications: 14756676; Phenotypes: Meleda disease, OMIM:248300; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova Phenotypes for gene: SLURP1 were changed from Mal de Meleda to Meleda disease, OMIM:248300
Peroxisomal disorders v1.16 SCP2 Zornitza Stark reviewed gene: SCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 16685654, 26497993; Phenotypes: Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v2.503 CACNA2D1 Konstantinos Varvagiannis reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35293990, 28097321; Phenotypes: Abnormal muscle tone, Feeding difficulties, Global developmental delay, Intellectual disability, Seizures, Microcephaly, Abnormality of the corpus callosum, Cerebral atrophy, Abnormality of movement, Cortical visual impairment, Pain insensitivity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1525 CACNA2D1 Konstantinos Varvagiannis gene: CACNA2D1 was added
gene: CACNA2D1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990; 28097321
Phenotypes for gene: CACNA2D1 were set to Abnormal muscle tone; Feeding difficulties; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of movement; Cortical visual impairment; Pain insensitivity
Penetrance for gene: CACNA2D1 were set to Complete
Review for gene: CACNA2D1 was set to GREEN
Added comment: Consider inclusion in the current panel with green rating.

Recent report of 2 unrelated individuals with DEE due to biallelic CACNA2D1 variants. Both referred to neurology/genetics for hypotonia/severe DD prior to onset of seizures.

One further individual with hypotonia and severe ID (seizures not discussed, age unknown).

Gene with established role, encoding α2δ-1 subunit of Cav channels. Studies for the variants support loss-of-function as the underlying effect.

Eventual contribution of monoallelic variants to NDD-phenotypes discussed (and put in question) in Ref [1] below.

There is currently no phenotype for CACNA2D1 in OMIM/G2P. In SysID this gene is listed among the candidates for ID, based on a previous report. CACNA2D1 is not currently included in the ID/epilepsy panels in PanelApp Australia.

See also relevant review in epilepsy panel (Dr. H. Lord).

Please consider also inclusion in other panels (e.g. microcephaly, corpus callosum, movement disorders, etc).

[1] ----
Dahimene et al (2022 - PMID: 35293990) describe the phenotype of 2 unrelated individuals with biallelic CACNA2D1 variants.

Overall, the phenotype corresponded to an early-onset DEE, characterized by abnormal muscle tone (axial hypotonia 2/2 with spasticity in extremities in 2/2), feeding difficulties (2/2), profound DD and ID (2/2), microcephaly (2/2 - approx. -2 SD in both), seizures (2/2 - 1st : onset 9m with absences and later generalized seizures, 2nd : onset 11m with hemi-clonic seizures and atypical absences). Other features included cortical visual impairment (2/2) and movement disorder (incl. choreiform movements 2/2, orofacial dyskinesia 2/2 and dystonic episodes 1/2). Brain MRI revealed corpus callosum anomalies (2/2) and cerebral atrophy (2/2). Both had echocardiography (abnormal in 1/2 - tiny PFO) and electrocardiography which was normal. Both exhibited insensibility to pain.

Presentation is relevant to the current panel as first symptoms in the first 3 months with severe hypotonia and poor head control (2/2) with evaluation in neurology/genetics preceding onset of seizures in both.

Trio ES was performed for both individuals and their (healthy) parents and revealed homozygosity for a fs variant in the first [NM_000722.3:c.818_822dup / p.(Ser275Asnfs*13)] and compound htz for a fs and a missense variant [c.13_23dup / p.(Leu9Alafs*5) and c.626G>A / p.(Gly209Asp)] in the second affected individual, respectively.

Eventual additional variants were not discussed.

Previous investigations are only provided for the 2nd and were all normal (karyotype, CMA, 15q methylation, epilepsy/neurometabolic gene panels).

Voltage-gated calcium channels are heteromultimers comprising different subunits incl. an alpha-1 (α1), α2δ (alpha-2/delta), beta (β) and gamma (γ). CACNA2D1 is one of the 4 genes (CACNA2D1-4) encoding the alpha-2/delta subunit. Its product is post-translationally processed into 2 peptides, an alpha-2 and a delta subunit, held by a disulfide bond.

Biallelic variants in CACNA2D2 - also encoding an alpha-2/delta subunit - cause cerebellar atrophy with seizures and variable developmental delay (# 618501).

Variant studies support loss-of-function effect for the studied variants, notably by NMD for the fs one, and severe impairment of the Cav2 channel function for the missense one :
- CACNA2D1 mRNA was reduced to 6-9% compared with control in fibroblasts from the 1st individual. mRNA levels for the 2nd subject were similar to control.
- Quantification of the protein in whole-cell lysates from fibroblasts revealed lower α2δ levels compared to control (10-12% and 31-38% applying to the 1st and 2nd individual).
- CACNA2D3 mRNA levels in fibroblasts from the 2nd patient were 2-7x higher compared to the 1st or controls suggesting a possible compensatory effect. CACNA2D2/4 mRNA levels were too low for quantification.
- Gly209 lies within the gabapentin and amino-acid binding pocket and this residue is invariable in CACNA2D1/CACNA2D2 in all vertebrates and paralogs.
- Transfection of tsA-201 cells with either WT or G209D HA-tagged α2δ revealed reduced cell surface expression for this missense variant (~80, for biotinylated form ~86%).
- In tsA-201 cells transfected with HA-tagged Cav2.2/β1b and either α2δ-1-WT, no α2δ-1 or α2δ-1-G209D, WT resulted in increased 13x currents with no increase applying to G209D (or in absence of α2δ). Plasma membrane expression of double (GFP/HA) tagged Cav2.2 was increased upon co-expression with WT α2δ-1 which was not the case for α2δ-1-G209D.
- In hippocampal neurons, double (GFP/HA)-tagged Cav2.2 could not be detected at the cell surface in the presence of α2δ-1-G209D (or no α2δ) in contrast with strong expression in presence of α2δ-1-WT. α2δ-1-G209D did not promote trafficking of Cav2.2 into hippocampal neurites, as indicated by reduced signals for both HA and GFP (for cell surface and total Cav2.2 respectively).
- Co-expression of double (GFP/HA) tagged Cav2.2 with β1b and either HA-α2δ-1-WT or HA-α2δ-1-G209D in tsA-201 cells, revealed reduced complex formation of G209D with Cav2.2 Co-immunoprecipitated HA-α2δ-1-G209D had higher molecular weight compared to HA-α2δ-1-WT which suggests that α2δ-1-G209D remains as the uncleaved immature form (probably in the ER).

Mouse model (several Refs in text):
Mild cardiac phenotype and reduced ventricular myocyte Ca current density was observed in hmz ko mice. Similarly to the insensibility to pain human phenotype, mice had delayed neuropathic pain-related responses. Overexpression of a2δ-1 resulted in epileptiform EEG and behavioral arrest, overall supporting a critical role of α2δ-1 for mouse brain.

The authors underscore that the parents of both patients (htz carriers) were healthy and review previous literature for association of monoallelic variants with epilepsy, ID and arrhythmogenic disorders (in suppl.) [Refs not here reviewed].

As for the NDD phenotype, CACNA2D1 is within a previously defined small region of overlap for 7q21.11 microdeletions associated with ID+/-epilepsy. The same study did not reveal de novo SNVs in any of the 3 contained genes within this SRO (HGF, CACNA2D1, PCLO) in 4293 patients with NDD [cited PMID: 28240412]. A frameshift variant (c.2625del) was identified in a 13-yo girl with infantile spasms and normal intelligence [cited PMID: 25877686]. A 1-bp insertion (c.659-2_659-1insT / not studied at the mRNA level) was identified in another 14-yo female with ID and epilepsy [cited PMID: 34356170]. The authors state that the phenotype (/differences) of these individuals as well as presence of pLoF CACNA2D1 variants in gnomAD [still pLI of 1] put in question pathogenicity of monoallelic variants for these phenotypes.

The role of heterozygous missense variants described in relation to arrhythmogenic disorders is also discussed extensively (some downgraded to LB/VUS, others having a relatively high MAF and presence of 1-2 homozygotes in gnomAD).

[2] ----
In an article cited by SysID for CACNA2D1 (2017 - PMID: 28097321), Reuter et al studied with WES and autozygosity mapping individuals with NDD belonging to consanguineous families.

As in eTables1/3, a male - single affected individual born to consanguineous parents from Turkey (MR150) - was investigated by singleton ES.

This individual was homozygous for a missense CACNA2D1 SNV [NM_000722.2:c.1514C>T;p.(Thr505Ile)].

Prior investigations are unavailable (although individuals with previously known P/LP CNVs were excluded).

The phenotype - briefly reported - included hypotonia, severe ID, stereotypic behaviors, inguinal hernia and omphalocele. Presence of seizures was not commented on. The age of this individual was not reported.
Sources: Literature, Other
Intellectual disability v3.1525 ACTL6B Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 76, OMIM:618468; Intellectual developmental disorder with severe speech and ambulation defects, OMIM:618470
Genetic epilepsy syndromes v2.503 ACTL6B Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Developmental and epileptic encephalopathy 76, OMIM:618468
Hereditary spastic paraplegia - childhood onset v2.131 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Hereditary spastic paraplegia - childhood onset v2.131 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Childhood onset dystonia or chorea or related movement disorder v1.218 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Childhood onset dystonia or chorea or related movement disorder v1.218 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Intellectual disability v3.1524 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Intellectual disability v3.1524 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
White matter disorders and cerebral calcification - narrow panel v1.227 ACER3 Arina Puzriakova Classified gene: ACER3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.227 ACER3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green on this panel at the next GMS review - now at least 5 unrelated families reported with homozygous variants (PMIDs: 26792856; 32816236; 34281620). Phenotypes that are consistent amongst all affected individuals comprise of developmental regression (motor and cognitive), dystonia, spasticity, and leukodystrophy.
White matter disorders and cerebral calcification - narrow panel v1.227 ACER3 Arina Puzriakova Gene: acer3 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.226 ACER3 Arina Puzriakova Publications for gene: ACER3 were set to 32816236; 26792856
White matter disorders and cerebral calcification - narrow panel v1.225 ACER3 Arina Puzriakova Tag watchlist was removed from gene: ACER3.
Tag Q1_22_rating tag was added to gene: ACER3.
White matter disorders and cerebral calcification - narrow panel v1.225 ACER3 Arina Puzriakova reviewed gene: ACER3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34281620; Phenotypes: Leukodystrophy, progressive, early childhood-onset, OMIM:617762; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.225 ACER3 Arina Puzriakova Phenotypes for gene: ACER3 were changed from ?Leukodystrophy, progressive, early childhood-onset, OMIM:617762 to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Intellectual disability v3.1523 TRAPPC10 Konstantinos Varvagiannis reviewed gene: TRAPPC10: Rating: AMBER; Mode of pathogenicity: None; Publications: 35298461, 30167849; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Gait disturbance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial pulmonary fibrosis v1.28 ACD Arina Puzriakova Tag watchlist_moi tag was added to gene: ACD.
Familial pulmonary fibrosis v1.28 ACD Arina Puzriakova Mode of inheritance for gene: ACD was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial pulmonary fibrosis v1.27 ACD Arina Puzriakova Classified gene: ACD as Green List (high evidence)
Familial pulmonary fibrosis v1.27 ACD Arina Puzriakova Added comment: Comment on list classification: This gene was approved by the NHS Genomic Medicine Service, rated green on the 'Pulmonary fibrosis familial' GMS panel with 'monoallelic' inheritance. Therefore the MOI and rating on this panel was also updated accordingly and the 'watchlist' tag was removed. Added 'watchlist_MOI' tag to ensure monitoring of biallelic variants as currently no evidence linking these to PF is available but may emerge in the future.
Familial pulmonary fibrosis v1.27 ACD Arina Puzriakova Gene: acd has been classified as Green List (High Evidence).
Familial pulmonary fibrosis v1.26 ACD Arina Puzriakova Tag watchlist was removed from gene: ACD.
Pulmonary fibrosis familial v0.6 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Dyskeratosis congenita, autosomal dominant, OMIM:6 to Dyskeratosis congenita, autosomal dominant, OMIM:616553
Pulmonary fibrosis familial v0.5 ACD Arina Puzriakova Publications for gene: ACD were set to
Cholestasis v1.106 AP1S1 Ivone Leong Classified gene: AP1S1 as Red List (low evidence)
Cholestasis v1.106 AP1S1 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert review by Miranda Durkie (Genetics).
Cholestasis v1.106 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Red List (Low Evidence).
Cholestasis v1.105 AP1S1 Ivone Leong Tag Q2_21_rating was removed from gene: AP1S1.
Pancreatitis v2.16 CEL Ivone Leong Classified gene: CEL as Amber List (moderate evidence)
Pancreatitis v2.16 CEL Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review by Miranda Durkie. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.
Pancreatitis v2.16 CEL Ivone Leong Gene: cel has been classified as Amber List (Moderate Evidence).
Pancreatitis v2.15 CEL Ivone Leong Phenotypes for gene: CEL were changed from to Hereditary Pancreatitis
Pancreatitis v2.14 CEL Ivone Leong Publications for gene: CEL were set to 29233499; 28881607; 28500240; 27802312; 27650499; 27773618; 26946345; 25774637; 23770712
Pancreatitis v2.13 CEL Ivone Leong Mode of inheritance for gene: CEL was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v2.502 RELN Sarah Leigh Phenotypes for gene: RELN were changed from {Epilepsy, familial temporal lobe, 7} 616436 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436
Genetic epilepsy syndromes v2.501 RELN Sarah Leigh Publications for gene: RELN were set to 26046367
Intellectual disability v3.1523 SLC12A5 Sarah Leigh reviewed gene: SLC12A5: Rating: ; Mode of pathogenicity: None; Publications: 24928908, 24668262, 26333769; Phenotypes: Developmental and epileptic encephalopathy 34, OMIM:616645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1523 SLC12A5 Sarah Leigh Publications for gene: SLC12A5 were set to 24668262; 26333769
Intellectual disability v3.1522 SLC12A5 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SLC12A5.
Intellectual disability v3.1522 SLC12A5 Sarah Leigh Phenotypes for gene: SLC12A5 were changed from FEBRILE SEIZURES to Developmental and epileptic encephalopathy 34, OMIM; 616645
Intellectual disability v3.1521 SLC12A5 Sarah Leigh Publications for gene: SLC12A5 were set to 24668262
Brain channelopathy v1.78 KCNMA1 Sarah Leigh reviewed gene: KCNMA1: Rating: ; Mode of pathogenicity: None; Publications: 29545233, 27567911; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.42 KCNMA1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: KCNMA1.
Paroxysmal central nervous system disorders v1.42 KCNMA1 Sarah Leigh reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29545233, 27567911; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.42 KCNMA1 Sarah Leigh Publications for gene: KCNMA1 were set to 15937479; 26195193
Neurodegenerative disorders - adult onset v2.268 CACNA1A_CAG Louise Daugherty reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.289 CACNA1A_CAG Louise Daugherty reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.289 ATXN10_ATTCT Louise Daugherty reviewed STR: ATXN10_ATTCT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v2.539 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from Immunodeficiency 14,615513; Combined immunodeficiency; Unclassified antibody deficiency; Activated PI3K-delta syndrome (APDS); sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections; decreased or absent pro-B cells, EBV; Predominantly Antibody Deficiencies to Immunodeficiency 14A, autosomal dominant, OMIM:615513; Immunodeficiency 14B, autosomal recessive, OMIM:619281; Combined immunodeficiency; Activated PI3K-delta syndrome (APDS); Predominantly Antibody Deficiencies; Sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections
COVID-19 research v1.118 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from Combined immunodeficiency; Activated PI3K-delta syndrome (APDS); Unclassified antibody deficiency; decreased or absent pro-B cells, EBV; Predominantly Antibody Deficiencies; sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections; Immunodeficiency 14,615513 to Immunodeficiency 14A, autosomal dominant, OMIM:615513; Immunodeficiency 14B, autosomal recessive, OMIM:619281; Combined immunodeficiency; Activated PI3K-delta syndrome (APDS); Predominantly Antibody Deficiencies; Sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections
Gastrointestinal epithelial barrier disorders v1.71 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from to Immunodeficiency 14B, autosomal recessive, OMIM:619281
Gastrointestinal epithelial barrier disorders v1.70 PIK3CD Arina Puzriakova Mode of inheritance for gene: PIK3CD was changed from to BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.56 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from Immunodeficiency 14, 615513; Bronchiectasis to Immunodeficiency 14A, autosomal dominant, OMIM:615513; Bronchiectasis
Non-CF bronchiectasis v1.27 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from to Immunodeficiency 14A, autosomal dominant, OMIM:615513
Infantile enterocolitis & monogenic inflammatory bowel disease v1.37 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from PI3K activation syndrome; Immunodeficiency 14 615513 to Immunodeficiency 14A, autosomal dominant, OMIM:615513
Genetic epilepsy syndromes v2.500 CACNA2D1 Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously providing a critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Genetic epilepsy syndromes v2.500 CACNA2D1 Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin

Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Genetic epilepsy syndromes v2.500 CACNA2D1 Helen Lord gene: CACNA2D1 was added
gene: CACNA2D1 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990
Phenotypes for gene: CACNA2D1 were set to Early onset developmental epilepsy
Review for gene: CACNA2D1 was set to AMBER
Added comment: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin

Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Genetic epilepsy syndromes v2.500 KCNC2 Helen Lord reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314505; Phenotypes: epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.844 MYH6 Ivone Leong Tag Q1_22_MOI tag was added to gene: MYH6.
Corneal abnormalities v1.12 TGFBI Ivone Leong Tag Q1_22_MOI tag was added to gene: TGFBI.
Intellectual disability v3.1520 ZNF292 Rachel Challis reviewed gene: ZNF292: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31723249; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Bleeding and platelet disorders v1.35 F7 Arina Puzriakova commented on gene: F7
Inherited bleeding disorders v1.164 F12 Arina Puzriakova commented on gene: F12
Bleeding and platelet disorders v1.35 F12 Arina Puzriakova commented on gene: F12
Vascular skin disorders v1.48 F12 Arina Puzriakova commented on gene: F12
COVID-19 research v1.117 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from hereditary angioedema; Angioedema, Hereditary, Type III to Angioedema, hereditary, 3, OMIM:610618
Primary immunodeficiency v2.538 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Angioedema, Hereditary, Type III; hereditary angioedema to Angioedema, hereditary, 3, OMIM:610618
Severe Paediatric Disorders v1.118 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Factor XII deficiency, 234000; Angioedema, hereditary, type III, 610618 to Angioedema, hereditary, 3, OMIM:610618; Factor XII deficiency, OMIM:234000
Pancreatitis v2.12 CEL Miranda Durkie reviewed gene: CEL: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 16369531, PMID: 34850019; Phenotypes: Hereditary Pancreatitis, Diabetes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cholestasis v1.105 AP1S1 Miranda Durkie reviewed gene: AP1S1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32306098; Phenotypes: Congenital diarrhoea; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v2.500 NAPB Tracy Lester gene: NAPB was added
gene: NAPB was added to Genetic epilepsy syndromes. Sources: NHS GMS
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
Review for gene: NAPB was set to GREEN
Added comment: Three cases reported with early infantile epileptic encepahlopathy and with homozygous LOF variants in this gene. Null mice also develop severe recurrent epileptic seizures from day 11, followed by ataxia. Sufficient evidence to be considered as green gene on the epilepsy and ID panels, autosomal recessive inheritance only.
Sources: NHS GMS
Intellectual disability v3.1520 PAN2 Konstantinos Varvagiannis gene: PAN2 was added
gene: PAN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y
Phenotypes for gene: PAN2 were set to Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck
Penetrance for gene: PAN2 were set to Complete
Review for gene: PAN2 was set to AMBER
Added comment: 1.
Maddirevula et al (2018 - PMID: 29620724) first reported on the phenotype associated with biallelic pathogenic variants in PAN2.

This concerned a male (15DG2222) born to consanguineous parents and exhibiting MCA, dysmorphic features and global DD (age of 34 m). Features incl. imperforate anus, metopic craniosynostosis, scoliosis, CHD (PFO, PDA, VSD), renal anomalies (duplicated collecting system) and abnormalities of the eye (posterior embryotoxon, maculopathy).

As the other 411 individuals from the cohort, the child had 1st-tier testing genetic testing using a dysmorphology/skeletal dysplasia panel of 296 genes.

Subsequent autozygome analysis (Axiom genotyping platform) was used to identify ROH (authors state "segregating within the family", in pedigree the proband was the single affected person and single child).

WES revealed a PAN2 indel. [NM_001166279.1:c.3162delC / p.(Ser1055Profs*4)].

There were no additional studies.

Role of PAN2 and animal models discussed as below.
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2.
Reuter et al. (2022 - https://doi.org/10.1038/s41431-022-01077-y) describe the phenotype of 5 additional individuals - from 3 unrelated families (2 consanguineous) - harboring biallelic PAN2 variants. The authors review the phenotype of the previously described case.

Features included DD (6/6), ID (4/5 with relevant age in the mild-moderate range, 1/5 had borderline IF), sensorineural hearing loss (5/6) and incompletely penetrant congenital anomalies of the heart (4/6 - TOF, septal defects, Ao root dilat), urinary malformations (4/6 - hypoplasia/agenesis, anovesical fistula), ophthalmological anomalies (2/6 - Rieger, posterior embryotoxon, etc). EEG anomalies or seizures were noted in 4/6. Craniofacial feat. in >=2/6 included cleft palate/bifid uvula, ptosis, hypertelorism, abn. of the nose, low-set ears, short neck. There was no comprehensive evaluation for skeletal dysplasia despite short stature/skeletal anomalies in multiple individuals. Hematological anomalies were reported in 2, possibly explained by another concurrent diagnosis (of GSD) in one individual.

WGS was performed for 1 individual, and WES for 4 members of the 2nd family and the proband in the 3rd. ROH identified in all 3 families (1 non-consanguineous but from the same region of Italy) are mentioned in the suppl. Sanger sequencing for parents and affected/unaffected sibs was mentioned for the 2 families with solo WGS/WES. One individual had a dual - previously established - diagnosis (of SLC37A4-related GSD) not related to his NDD. There were no other candidate variants except for VUS or variants in 'genes of uncertain significance'.

The majority of mammalian mature mRNAs have polyA tails, added during RNA processing. PAN2 encodes a subunit of the Pan2-Pan3 deadenylation complex which shortens mRNA 3' polyA tails, regulating mRNA stability/translation efficiency.

Specifically Pan2 is the catalytic subunit, while the interaction with Pan3 mediates efficient mRNA binding. Deadenylation in cytoplasm is mostly carried out by the Pan2-Pan3 or Ccr4-Not compexes. While perturbations of mRNA metabolism/decay are established causes of NDD and ID. In particular, monoallelic variants in genes of Ccr4-Not complex (inc. CNOT1/2/3) already causative of NDDs.

All affected individuals were homozygous for pLoF PAN2 variants, namely (NM_001166279.2): c.2335G>T / p.(Glu779*) [Fam1], c.3408dupT / p.(Glu1137*) [Fam2], c.574-2A>G / p.? [Fam3].

Variants were absent from gnomAD (where PAN2 has a pLI:0.94, o/e:0.19).

There were no variant studies performed. The splicing variant is predicted in silico to abolish the splice-acceptor site, with in-frame skippling of ex5 which codes a repeat within the WD40 domain. Previous studies in yeast have shown that this domain is important for sensing the length of the polyA tail, with absence of this domain resulting in impaired deadenylation of 90A tails (similarly to complete Pan2 del) [cited PMID: 31104843].

Overall PAN2 loss-of-function is thought to be the underlying disease mechanism.

Partial functional redundancy of Pan2/Pan3 (initiation of deadenylation) and Ccr4-Not complexes (further shortening of polyA) is speculated to mitigate consequences of PAN2 LoF in humans.

In yeast Pan2Δ, Ccr4Δ and Pan2Δ/Ccr4Δ have been studied with more severe phenotypes in double mutants where ability to shorten mRNA polyA tails was abolished [cited PMID:11239395]. In yeast extracts lacking Pan2p and Pan3p, transcripts were polyadenylated to >90-200 adenosines [cited PMID: 9774670]

Mouse mutants (MGI:1918984) had increased heart weight, increased eosinophil cell number while homozygosity for a stopgain allele (by ENU mutagenesis) was shown to result in embyonic lethality.

Finally, given the presence of thrombocytopenia and anemia in 3 individuals (2 families) as well as the link between mRNA deadenylation and telomere disease, telomere length analyses from WGS data were performed (TelSeq/Expansion Hunter dn), but there was no evidence for telomeric shortening.
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Currently, there is no PAN2-related phenotype in OMIM/G2P/SysID/PanelApp Australia.
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Consider inclusion in the ID panel with amber rating [>3 individuals/families/variants, though variant studies not performed (NMD/splicing) and authors of 2nd study recognize possibility of additional/concurrent diagnoses in individuals from consanguineous families, possibility of missed dn variants due to singleton WGS/WES in 2 fam. Also the presumed deadenylation defect not studied to date].

Please consider adding this gene to other panels - eg. for sens. hearing loss (5/6 - 3 fam), urinary tract anomalies (4/6 - 4 fam), congenital (4/6 - 3fam), anorectal malformations (2/6 - 2 families, incl. fistula or imperforate anus), clefting (2/6 - 1 fam), hematological disorders, etc.

For the time being, not added in epilepsy panel as some individuals had only EEG anomalies, few had also clinical seizures not necessarily requiring treatment.
Sources: Literature
Hereditary neuropathy NOT PMP22 copy number v1.88 PCYT2 Dmitrijs Rots gene: PCYT2 was added
gene: PCYT2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to PMID: 35243002
Review for gene: PCYT2 was set to AMBER
Added comment: Two brother with axonal neuropathy reported in PMID: 35243002. In the same study, after reviewing previously published cases, other individuals (2/10) had sensory deficit / neuropathy: "Of 5 previously reported adult patients (age range of 20–59 years),2-6 nerve conduction studies were performed in 2 of them and reported as normal.3,4 Clinically, one of them had hypopallesthesia of the ankles,4 and the other had loss of vibration sense in the lower limbs and mild loss of proprioception in the feet".
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v1.78 FDX2 Dmitrijs Rots reviewed gene: FDX2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35079622; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1520 HIST1H4C Konstantinos Varvagiannis reviewed gene: HIST1H4C: 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: 28920961, 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1, #619758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4J Konstantinos Varvagiannis reviewed gene: HIST1H4J: 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: 31804630, 35202563; Phenotypes: ?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4D Konstantinos Varvagiannis gene: HIST1H4D was added
gene: HIST1H4D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4D were set to 35202563
Phenotypes for gene: HIST1H4D were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4D were set to Complete
Mode of pathogenicity for gene: HIST1H4D 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: HIST1H4D was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

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Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

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In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

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Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

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[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4E Konstantinos Varvagiannis gene: HIST1H4E was added
gene: HIST1H4E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4E were set to 35202563
Phenotypes for gene: HIST1H4E were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4E were set to unknown
Mode of pathogenicity for gene: HIST1H4E 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: HIST1H4E was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4F Konstantinos Varvagiannis gene: HIST1H4F was added
gene: HIST1H4F was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4F were set to 35202563
Phenotypes for gene: HIST1H4F were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4F were set to unknown
Mode of pathogenicity for gene: HIST1H4F 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: HIST1H4F was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4I Konstantinos Varvagiannis gene: HIST1H4I was added
gene: HIST1H4I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4I were set to 35202563
Phenotypes for gene: HIST1H4I were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4I were set to unknown
Mode of pathogenicity for gene: HIST1H4I 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: HIST1H4I was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Skeletal dysplasia v2.190 DVL2 Michael Oldridge gene: DVL2 was added
gene: DVL2 was added to Skeletal dysplasia. Sources: Expert Review
Mode of inheritance for gene: DVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DVL2 were set to PMID: 35047859
Phenotypes for gene: DVL2 were set to autosomal dominant Robinow sydrome
Penetrance for gene: DVL2 were set to Complete
Mode of pathogenicity for gene: DVL2 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: DVL2 was set to GREEN
Added comment: De novo fs variant in final exon of DVL2 identified in patient with clinical diagnosis of Robinow syndrome. This leads to a 103 residue missense tail extending beyond the WT stop codon. A number of similar fs variants have been identified in DVL1 and DVL3 leading to autosomal dominant Robinow syndrome; these variants also lead to extended missense tails and are therefore thought to act via a very specific gain of function mechanism (LOF variants in these genes do not lead to Robinow). DVL1, 2 and 3 share considerable homology (59-67%) and have overlapping function during development.
Only reported in 1 case but the very specific nature of the mutation explains rareity. Should be tested as Green.
Sources: Expert Review
Ocular coloboma v1.46 RARB Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as biallelic variants also cause disease.
Ocular coloboma v1.46 RARB Ivone Leong Mode of inheritance for gene: RARB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.45 SIX6 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BIALLELIC, autosomal or pseudoautosomal".

Review copied from Structural eye disease panel:
"Aldamesh (2013) reported one family; Yariz (2015) one family; Patel (2018) one family), all three variants homozygous. Gallardo reported a heterozygous variant in a patient with bilateral microphthalmia, inherited from the unaffected father. This variant has now been reclassified on OMIM as VUS. Mode of inheritance should be changed.
Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust), 19 Jun 2019"
Anophthalmia or microphthalmia v1.45 SIX6 Ivone Leong Mode of inheritance for gene: SIX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.44 SIX6 Ivone Leong Phenotypes for gene: SIX6 were changed from Anophthalmia/Microphthalmia; Microphthalmia with cataract 2, 212550 to Optic disc anomalies with retinal and/or macular dystrophy, OMIM:212550
Corneal dystrophies v1.10 TGFBI Ivone Leong reviewed gene: TGFBI: Rating: ; Mode of pathogenicity: None; Publications: 31322463, 30830990, 32952948; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Corneal abnormalities v1.12 TGFBI Ivone Leong Added comment: Comment on publications: New publications added: 31322463, 30830990, 32952948
Corneal abnormalities v1.12 TGFBI Ivone Leong Publications for gene: TGFBI were set to 11146721; 15531312; 16652336; 9780098; 9727509
Corneal abnormalities v1.11 TGFBI Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more severe disease)".
Corneal abnormalities v1.11 TGFBI Ivone Leong Mode of inheritance for gene: TGFBI 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
Familial non syndromic congenital heart disease v1.75 MYH6 Ivone Leong Added comment: Comment on mode of inheritance: MOI change dfrom "BIALLELIC, autosomal or pseudoautosomal" to "Both Monoallelic and Biallelic" as Monoallelic variants also cause disease.
Familial non syndromic congenital heart disease v1.75 MYH6 Ivone Leong Mode of inheritance for gene: MYH6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.844 MYH6 Ivone Leong reviewed gene: MYH6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inborn errors of metabolism v2.234 QARS Sarah Leigh Mode of inheritance for gene: QARS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.233 QARS Sarah Leigh Mode of inheritance for gene: QARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.233 QARS Sarah Leigh Publications for gene: QARS were set to
Mitochondrial disorders v2.95 GATC Sarah Leigh Phenotypes for gene: GATC were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Combined oxidative phosphorylation deficiency 42, OMIM:618839
Mitochondrial disorders v2.94 GATC Sarah Leigh Mode of inheritance for gene: GATC was changed from to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.232 GATC Sarah Leigh Added comment: Comment on phenotypes: Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Inborn errors of metabolism v2.232 GATC Sarah Leigh Phenotypes for gene: GATC were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Combined oxidative phosphorylation deficiency 42, OMIM:618839
Inborn errors of metabolism v2.231 GATC Sarah Leigh Mode of inheritance for gene: GATC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.83 UNC45B Sarah Leigh commented on gene: UNC45B: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Congenital myopathy v2.83 UNC45B Sarah Leigh Deleted their comment
Congenital myopathy v2.83 UNC45B Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: UNC45B.
Congenital myopathy v2.83 UNC45B Sarah Leigh Classified gene: UNC45B as Amber List (moderate evidence)
Congenital myopathy v2.83 UNC45B Sarah Leigh Gene: unc45b has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.82 KY Sarah Leigh Deleted their comment
Congenital myopathy v2.82 KY Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: KY.
Congenital myopathy v2.82 KY Sarah Leigh Classified gene: KY as Amber List (moderate evidence)
Congenital myopathy v2.82 KY Sarah Leigh Added comment: Comment on list classification: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Congenital myopathy v2.82 KY Sarah Leigh Gene: ky has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.81 KY Sarah Leigh Deleted their comment
Congenital myopathy v2.81 GFER Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: GFER.
Congenital myopathy v2.81 GFER Sarah Leigh Classified gene: GFER as Amber List (moderate evidence)
Congenital myopathy v2.81 GFER Sarah Leigh Gene: gfer has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.80 GFER Sarah Leigh reviewed gene: GFER: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.80 GFER Sarah Leigh Deleted their review
Intellectual disability v3.1520 GLS Arina Puzriakova Tag for-review was removed from gene: GLS.
Tag watchlist tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.514 GLS Arina Puzriakova Tag watchlist tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.514 GLS Arina Puzriakova Tag for-review was removed from gene: GLS.
Renal ciliopathies v1.61 DLG5 Eleanor Williams commented on gene: DLG5: Changed the mode of inheritance to be inline with that recommended by the NHS reviewer. Removed the Q3_21_MOI and Q3_21_NHS_review tags.
Renal ciliopathies v1.61 DLG5 Eleanor Williams Tag Q3_21_MOI was removed from gene: DLG5.
Tag Q3_21_NHS_review was removed from gene: DLG5.
Renal ciliopathies v1.61 DLG5 Eleanor Williams Mode of inheritance for gene: DLG5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia - adult onset v2.149 ABCB7 Eleanor Williams Added comment: Comment on mode of inheritance: Changed the mode of inheritance now this gene has been demoted to amber on this panel and removed the Q3_21_MOI tag.
Hereditary ataxia - adult onset v2.149 ABCB7 Eleanor Williams Mode of inheritance for gene: ABCB7 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
Hereditary ataxia - adult onset v2.148 ABCB7 Eleanor Williams Tag Q3_21_MOI was removed from gene: ABCB7.
Ataxia and cerebellar anomalies - narrow panel v2.289 GLS Eleanor Williams commented on gene: GLS
Ataxia and cerebellar anomalies - narrow panel v2.289 GLS Eleanor Williams Tag for-review was removed from gene: GLS.
Tag watchlist tag was added to gene: GLS.
Multiple monogenic benign skin tumours v1.20 NOTCH3 Eleanor Williams commented on gene: NOTCH3: Removed the Q4_21_expert_review and Q4_21_NHS_review tags from this gene, and added the watchlist tag as it has only enough evidence for Amber at the moment. If more evidence is found to support the gene-disease association then the eligibility criteria for the panel needs to be expanded before promoting the gene to green.
Multiple monogenic benign skin tumours v1.20 NOTCH3 Eleanor Williams Tag Q4_21_expert_review was removed from gene: NOTCH3.
Tag Q4_21_NHS_review was removed from gene: NOTCH3.
Tag watchlist tag was added to gene: NOTCH3.
Genetic epilepsy syndromes v2.500 FAR1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline); to: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel.
Fetal anomalies v1.844 TUBA8 Arina Puzriakova Classified gene: TUBA8 as Amber List (moderate evidence)
Fetal anomalies v1.844 TUBA8 Arina Puzriakova Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.843 TUBA8 Arina Puzriakova Tag for-review was removed from gene: TUBA8.
Fetal anomalies v1.843 TUBA8 Arina Puzriakova commented on gene: TUBA8
Fetal anomalies v1.843 NEK9 Arina Puzriakova Classified gene: NEK9 as Green List (high evidence)
Fetal anomalies v1.843 NEK9 Arina Puzriakova Gene: nek9 has been classified as Green List (High Evidence).
Fetal anomalies v1.842 NEK9 Arina Puzriakova Tag for-review was removed from gene: NEK9.
Fetal anomalies v1.842 NEK9 Arina Puzriakova commented on gene: NEK9: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Skeletal dysplasia v2.190 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Intellectual disability v3.1520 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Familial non syndromic congenital heart disease v1.74 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Genetic epilepsy syndromes v2.500 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Clefting v2.66 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Intellectual disability v3.1520 ISCA-37423-Loss Arina Puzriakova commented on Region: ISCA-37423-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37423-Loss Arina Puzriakova commented on Region: ISCA-37423-Loss
Intellectual disability v3.1520 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss
Craniosynostosis v2.67 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Undiagnosed metabolic disorders v1.514 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Malformations of cortical development v2.137 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Mitochondrial disorders v2.93 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37430-Gain Arina Puzriakova commented on Region: ISCA-37430-Gain
Hereditary neuropathy v1.442 ISCA-37436-Gain Arina Puzriakova commented on Region: ISCA-37436-Gain
Intellectual disability v3.1520 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Genetic epilepsy syndromes v2.500 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Skeletal dysplasia v2.190 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Intellectual disability v3.1520 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Genetic epilepsy syndromes v2.500 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Inborn errors of metabolism v2.230 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Hereditary neuropathy v1.442 ISCA-37436-Loss Eleanor Williams commented on Region: ISCA-37436-Loss
Genetic epilepsy syndromes v2.500 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Growth failure in early childhood v1.101 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Paediatric motor neuronopathies v1.77 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Congenital myopathy v2.80 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
IUGR and IGF abnormalities v1.51 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Intellectual disability v3.1520 ISCA-46299-Gain Arina Puzriakova commented on Region: ISCA-46299-Gain
Intellectual disability v3.1520 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Skeletal dysplasia v2.190 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Severe microcephaly v2.294 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Deafness and congenital structural abnormalities v1.19 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Ataxia and cerebellar anomalies - narrow panel v2.289 ISCA-37478-Loss Eleanor Williams commented on Region: ISCA-37478-Loss
Intellectual disability v3.1520 ISCA-37494-Gain Arina Puzriakova commented on Region: ISCA-37494-Gain
Intellectual disability v3.1520 ISCA-37493-Loss Arina Puzriakova commented on Region: ISCA-37493-Loss
Neurodegenerative disorders - adult onset v2.268 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Genetic epilepsy syndromes v2.500 ISCA-37493-Loss Arina Puzriakova commented on Region: ISCA-37493-Loss
Intellectual disability v3.1520 ISCA-37494-Loss Arina Puzriakova commented on Region: ISCA-37494-Loss
Hereditary ataxia v1.299 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Intellectual disability v3.1520